{"gene":"PF3D7_1343700","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2013,"finding":"Mutations in the PF3D7_1343700 kelch propeller domain ('K13-propeller') are associated with artemisinin resistance in vitro and in vivo. Using whole-genome sequencing of an artemisinin-resistant parasite line and clinical isolates, mutant K13-propeller alleles were found to cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant allele correlates with the recent spread of resistance in western Cambodia.","method":"Whole-genome sequencing of artemisinin-resistant parasite line; in vitro parasite survival assays; in vivo parasite clearance rate measurements in patients","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (WGS, in vitro RSA, in vivo clearance) in a landmark study; independently replicated across many subsequent studies","pmids":["24352242"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"Genetic modification of the Kelch13 locus using zinc-finger nucleases demonstrated that K13 mutations are causally sufficient to confer artemisinin resistance. Removal of K13 mutations from resistant Cambodian isolates reduced ring-stage survival rates from 13–49% to 0.3–2.4%, while insertion of K13 mutations into wild-type parasites increased survival rates from ≤0.6% to 2–29%.","method":"Zinc-finger nuclease-mediated genetic modification of the Kelch13 locus in P. falciparum; ring-stage survival assay (RSA)","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct causal demonstration via reciprocal gene editing (insertion and removal of mutations) with functional phenotypic readout; landmark study independently replicated","pmids":["25502314"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Kelch13 (PfKelch13) binds to and promotes polyubiquitination and proteolysis of PfPI3K. The C580Y resistance mutation in Kelch13 reduces polyubiquitination of PfPI3K and its binding to Kelch13, limiting PfPI3K proteolysis and thereby increasing PfPI3K levels and its lipid product phosphatidylinositol-3-phosphate (PI3P). Elevated PI3P was shown to be predictive of artemisinin resistance.","method":"Biochemical binding assays; polyubiquitination assays; measurement of PfPI3K protein levels and PI3P lipid levels in resistant clinical strains vs. wild-type; in vitro and in vivo artemisinin susceptibility assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution of binding/ubiquitination, multiple orthogonal methods (protein levels, lipid levels, in vitro/in vivo drug assays), single lab but multiple method types","pmids":["25874676"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Kelch13 mutations result in decreased expression of the Kelch13 protein, and mislocalization of Kelch13 (using a knock-sideways approach) mimics resistance-conferring mutations, indicating that partial loss of function of Kelch13 is the relevant molecular event for resistance. Kelch13-GFP localizes to ~170 nm diameter doughnut-shaped structures at the parasite periphery consistent with cytostomes. Mislocalization of Kelch13 reduces the hemoglobin-peptide profile of ring-stage parasites and reduces disruption to protein turnover following artemisinin exposure.","method":"Mislocalization (knock-sideways) of Kelch13 using GFP tagging; fluorescence microscopy; pulse-SILAC protein turnover quantification; peptidomics of hemoglobin-derived peptides","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, multiple orthogonal methods (microscopy, proteomics, peptidomics), single lab","pmids":["31775055"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"Using selection-linked integration (SLI), Kelch13 was localized and inducibly inactivated in P. falciparum. Inducible inactivation of Kelch13 demonstrated it is an essential protein. The SLI approach allowed functional analysis at gene and protein levels including mislocalization of the native protein.","method":"Selection-linked integration (SLI) for genomic integration; knock-sideways mislocalization; DiCre-based conditional gene excision; fluorescence microscopy","journal":"Nature methods","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct inactivation/mislocalization experiment with functional readout (essentiality confirmed), single lab, single study","pmids":["28288121"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Kelch13 defines a specific endosomal/vesicular compartment in P. falciparum. Inactivation of Kelch13 or expression of a resistance-conferring Kelch13 mutation reduced hemoglobin endocytosis from the host red cell. Since artemisinins are activated by hemoglobin degradation products (heme), reduced hemoglobin endocytosis caused by Kelch13 dysfunction leads to decreased artemisinin activation and parasite resistance. Eight Kelch13-compartment proteins were identified whose inactivation also rendered parasites resistant to artemisinin.","method":"Identification of Kelch13-compartment proteins; genetic inactivation of Kelch13 and interactors; hemoglobin endocytosis assays; ring-stage survival assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple proteins tested by genetic inactivation with specific cellular phenotype (hemoglobin endocytosis), resistance-conferring mutation validated, multiple orthogonal methods, independently supported by other studies","pmids":["31896710"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Kelch13 localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes (which traffic hemoglobin to the digestive vacuole). Upon treatment with dihydroartemisinin, Kelch13 partially relocalizes near the parasite mitochondria. Immunoprecipitation with Kelch13-specific monoclonal antibodies identified multiple putative Kelch13-associated proteins including ER-resident molecules, mitochondrial proteins, and Rab GTPases. Co-expression of wild-type Kelch13 reversed mutant Kelch13-mediated resistance.","method":"K13-specific monoclonal antibodies; gene-edited parasite lines co-expressing epitope-tagged Kelch13; quantitative imaging pipeline; immunoprecipitation; fluorescence microscopy; ring-stage survival assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation with specific antibodies, localization confirmed by multiple orthogonal approaches (antibodies + tagged lines + imaging pipeline), resistance reversal experiment, single lab with multiple methods","pmids":["32310999"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"Kelch13 concentrates at PI3P tubules/vesicles of the parasite's endoplasmic reticulum in infected red cells. Kelch13 colocalizes and copurifies with the major virulence adhesin PfEMP1. The C580Y resistance mutation quantitatively increased PI3P tubules/vesicles, exporting them throughout the parasite and the red cell. Multiple Kelch13 mutants showed alterations in PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor.","method":"Cryoimmunoelectron microscopy; colocalization and copurification experiments; PI3P vesicle quantification; PfEMP1 export and cytoadherence assays in K13 mutant parasites","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cryo-immunoEM localization, copurification evidence, multiple K13 mutant lines tested, single lab","pmids":["29363540"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"Multi-omics profiling of PfKelch13-mutant artemisinin-resistant vs. sensitive P. falciparum strains revealed that Kelch13 mutations are specifically associated with decreased abundance of Kelch13 protein itself, decreased hemoglobin digestion (lower abundance of hemoglobin-derived peptides), and enhanced glutathione production.","method":"LC-MS-based proteomics, peptidomics, and metabolomics of isogenic Kelch13 mutant and wild-type parasite lines","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal omics methods on isogenic lines, single lab, consistent mechanistic picture","pmids":["28368494"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"Systems-based quantitative transcriptomics, proteomics, and metabolomics applied to isogenic Kelch13 mutant and wild-type P. falciparum lines showed that Kelch13 mutations alter multiple aspects of the parasite's intra-erythrocytic developmental program, including cell-cycle periodicity, unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. Kelch13-mediated resistance in the Cambodian Cam3.II line was reversed by atovaquone (a mitochondrial electron transport chain inhibitor), implicating mitochondrial processes in resistance.","method":"Isogenic K13 mutant panel; quantitative transcriptomics, proteomics, and metabolomics; atovaquone reversal experiment; ring-stage survival assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal omics on isogenic panel plus functional reversal experiment, single lab, rigorous controls","pmids":["33483501"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"PfKelch13 protein is expressed ubiquitously in all asexual erythrocytic stages and in gametocytes, and localizes to punctate structures partially overlapping an endoplasmic reticulum marker. Introduction of four PfKelch13 mutations (F446I, N458Y, C469Y, F495L) from China-Myanmar border parasites into the 3D7 strain showed higher RSA survival rates, with N458Y yielding the most significant increase (26.3%). Reversion of these mutations in field isolates reduced RSA values. F446I caused prolonged ring-stage development with minimal fitness cost.","method":"GFP-tagging of PfKelch13; new anti-PfKelch13 antibody; fluorescence microscopy; CRISPR-based mutation introduction and reversion; ring-stage survival assay; in vitro culture competition assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with antibody and GFP tag, mutation introduction and reversion experiments with functional readout, single lab","pmids":["32098812"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2021,"finding":"Gene editing of multiple Kelch13 mutations (including R561H, C580Y, M579I) into African (3D7) and Southeast Asian (Dd2 and other) P. falciparum strain backgrounds showed that the resistance conferred by Kelch13 mutations depends on genetic background. C580Y and M579I cause substantial fitness costs in most backgrounds but not in recent Cambodian strains; R561H is fitness neutral in African 3D7 parasites. Only R561H yielded ART resistance comparable to C580Y when edited into Southeast Asian strains.","method":"Gene editing (introduction of K13 mutations into multiple strain backgrounds); ring-stage survival assay; mixed-culture fitness competition assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic gene editing across multiple strain backgrounds with both resistance and fitness readouts, multiple mutations tested, replication of key findings","pmids":["34279219"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"ART treatment induces growth retardation and accumulation of ubiquitinated proteins in wild-type parasites, indicative of a cellular stress response engaging the ubiquitin/proteasome system. Resistant parasites carrying K13 propeller mutations exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. Inhibiting the proteasome strongly synergizes ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type Kelch13.","method":"Kinetic analysis of drug responses; measurement of ubiquitinated protein levels; proteasome inhibitor synergy assays in K13 wild-type and mutant isogenic lines; P. berghei in vivo synergy experiments","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ubiquitin levels, cell death kinetics, drug synergy in isogenic lines), cross-validated in vivo in P. berghei, single lab","pmids":["25901609"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2017,"finding":"Kelch13 mutations (C580Y, R539T, I543T) confer cross-resistance to the ozonide OZ277 (arterolane) in addition to dihydroartemisinin. However, OZ439 (artefenomel) retains activity against most K13 mutant parasites (cross-resistance only observed for the rare I543T mutation). K13 mutations showed variable impacts on parasite growth rates depending on the specific mutation and parasite strain, with the prevalent C580Y mutation being fitness neutral in recently culture-adapted Cambodian strains.","method":"Ring-stage survival assay (RSA0-3h) with DHA, OZ439, and OZ277; mixed-culture competition experiments with isogenic K13 lines; gene-edited clinical isolates from Cambodia","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isogenic gene-edited lines, multiple drug treatments, reciprocal fitness competition assays, multiple K13 mutations tested","pmids":["28400526"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Gene editing confirmed that the Kelch13 R561H mutation drives artemisinin resistance in vitro in P. falciparum, providing evidence for de novo emergence of Kelch13-mediated artemisinin resistance in Rwanda.","method":"Gene editing (introduction of R561H mutation into P. falciparum); ring-stage survival assay","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct causal demonstration via gene editing with functional RSA readout, independently confirmed in multiple follow-up studies","pmids":["32747827"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"In vitro artemisinin resistance can emerge independently of Kelch13 mutations in P. falciparum, as shown by long-term in vitro selection that induced profound stage-specific resistance with no pfk13 mutations, associated instead with enhanced adaptive responses against oxidative stress and protein damage.","method":"Long-term in vitro selection for artemisinin resistance; chemosensitivity assays; transcriptional profiling; whole-genome sequencing","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative finding regarding Kelch13 mechanistically informative: resistance can arise without Kelch13 mutations; multiple orthogonal methods, single lab","pmids":["29538461"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2020,"finding":"In vitro emergence of Kelch13 C580Y mutations in Guyana (South America) in parasites with a genetic origin distinct from Southeast Asia was demonstrated. Introducing C580Y or R539T mutations by gene editing into local Guyanese parasites conferred high levels of in vitro artemisinin resistance. In vitro growth competition assays revealed a fitness cost associated with these Kelch13 variants.","method":"Genome analysis; gene editing (CRISPR) to introduce C580Y and R539T into local P. falciparum; ring-stage survival assay; in vitro growth competition assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct gene editing with functional phenotype and fitness readout, multiple mutations tested, single lab","pmids":["32394893"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"In vitro artemisinin resistance assay (delayed clearance assay/DCA) results correlated with parasite clearance half-life in vivo and with mutations in the Kelch13 domain gene (Pf3D7_1343700). Artemisinin-resistant P. falciparum parasites exhibited altered patterns of development resulting in reduced exposure to drug at the trophozoite stage and increased exposure in the ring stage, indicating an altered cell cycle mechanism for resistance.","method":"In vitro delayed clearance assay (DCA); stage-specific drug exposure quantification; correlation with in vivo clearance half-life; K13 genotyping","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assay correlated with in vivo phenotype and Kelch13 genotype, multiple isolates, single lab","pmids":["25779582"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"finding":"Introduction of globally dominant Kelch13 mutations (C580Y, R561H, F446I) by CRISPR-Cas9 into two Bangladeshi P. falciparum isolates (including a K13-independent resistant strain) demonstrated that C580Y and R561H confer marked increases in artemisinin resistance in both backgrounds, while F446I had only modest effects. R561H in the resistant background conferred extreme resistance (RSA 30.09%) and an asexual growth advantage. All three mutations incurred minimal fitness costs in the artemisinin-sensitive background.","method":"CRISPR-Cas9 gene editing; ring-stage survival assay; post-treatment recovery assays; competitive fitness assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct gene editing with functional RSA and fitness readouts, two parasite backgrounds tested, single lab, single study","pmids":["41841738"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"Kelch13 (PF3D7_1343700) is a BTB/POZ and kelch-propeller domain protein that localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes; it functions as a regulator of hemoglobin endocytosis (via the cytostome pathway) and promotes polyubiquitination and proteolysis of PfPI3K, thereby controlling PI3P levels and cellular proteostasis — resistance-conferring mutations in its propeller domain reduce Kelch13 protein abundance and function, leading to decreased hemoglobin uptake and heme-mediated artemisinin activation, attenuated proteotoxic stress responses, and elevated PI3P, collectively enabling ring-stage parasites to survive artemisinin exposure."},"narrative":{"mechanistic_narrative":"Kelch13 (PF3D7_1343700) is an essential BTB/POZ- and kelch-propeller-domain protein of Plasmodium falciparum that governs hemoglobin endocytosis and cellular proteostasis, and whose propeller-domain mutations are the principal genetic determinant of artemisinin resistance [PMID:24352242, PMID:25502314, PMID:31896710]. Reciprocal gene editing across multiple parasite backgrounds established that propeller-domain mutations (e.g. C580Y, R561H, R539T, M579I) are causally sufficient to confer ring-stage artemisinin survival, that their effect and fitness cost depend on genetic background, and that these alleles have emerged independently in Southeast Asia, Africa (Rwanda) and South America (Guyana) [PMID:25502314, PMID:34279219, PMID:32747827, PMID:32394893]. Mechanistically, Kelch13 defines an endosomal/vesicular compartment where it drives hemoglobin uptake from the host red cell via the cytostome pathway; because artemisinins are activated by hemoglobin-derived heme, mutation- or mislocalization-induced loss of Kelch13 function reduces hemoglobin endocytosis and thereby lowers drug activation, and this partial loss of function is accompanied by reduced Kelch13 protein abundance [PMID:31775055, PMID:31896710, PMID:28368494]. Kelch13 also binds PfPI3K and promotes its polyubiquitination and proteolysis, so that resistance mutations elevate PfPI3K and its lipid product PI3P, a change predictive of resistance and associated with altered PI3P vesicle/tubule networks and PfEMP1 export [PMID:25874676, PMID:29363540]. Consistent with a proteostasis role, artemisinin engages the ubiquitin/proteasome stress response, Kelch13-mutant parasites mount an attenuated proteotoxic response, and proteasome inhibition synergizes with artemisinin [PMID:25901609]; systems-level analyses link Kelch13 mutations to altered cell-cycle periodicity, the unfolded protein response, vesicular trafficking and mitochondrial metabolism [PMID:33483501]. Kelch13 localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes, and relocalizes toward the mitochondrion upon dihydroartemisinin exposure [PMID:31775055, PMID:32310999].","teleology":[{"year":2013,"claim":"Established the first genetic marker of artemisinin resistance by linking a specific parasite locus to the clinical phenotype, previously defined only by delayed parasite clearance.","evidence":"Whole-genome sequencing of a resistant line plus in vitro survival and in vivo clearance measurements in Cambodian isolates","pmids":["24352242"],"confidence":"High","gaps":["Association only — did not prove causality","No molecular function assigned to Kelch13","Mechanism of resistance unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Proved that Kelch13 propeller mutations are causally sufficient for resistance, moving the field from correlation to causation.","evidence":"Zinc-finger nuclease reciprocal editing (insertion and removal of mutations) with ring-stage survival readout","pmids":["25502314"],"confidence":"High","gaps":["Did not define the biochemical function of Kelch13","Did not identify how mutations alter protein activity"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Provided a biochemical mechanism by identifying PfPI3K as a Kelch13 target whose ubiquitin-dependent turnover controls PI3P, and mutations relieve this control.","evidence":"Binding and polyubiquitination assays plus PfPI3K/PI3P quantification in resistant strains and drug susceptibility assays","pmids":["25874676"],"confidence":"High","gaps":["Ubiquitin ligase machinery not fully defined","Relationship between PI3P elevation and hemoglobin/heme pathway not integrated","Single lab for the biochemical reconstitution"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Connected resistance to an attenuated proteotoxic stress response and revealed a therapeutic vulnerability via proteasome inhibition.","evidence":"Ubiquitinated-protein and cell-death kinetics plus proteasome-inhibitor synergy in isogenic lines, cross-validated in vivo in P. berghei","pmids":["25901609"],"confidence":"High","gaps":["Did not directly link Kelch13 to proteasome regulation mechanistically","Which stress-response components are Kelch13-dependent unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2017,"claim":"Confirmed Kelch13 essentiality and enabled functional dissection via inducible inactivation and mislocalization of the native protein.","evidence":"Selection-linked integration with DiCre excision and knock-sideways mislocalization plus microscopy","pmids":["28288121"],"confidence":"Medium","gaps":["Single lab, single study","Did not resolve the essential molecular activity","Essentiality vs. partial-loss-of-function distinction for resistance not addressed here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Multi-omics tied Kelch13 mutations to reduced Kelch13 protein, decreased hemoglobin digestion, and altered redox metabolism, foreshadowing the hemoglobin-uptake mechanism.","evidence":"LC-MS proteomics, peptidomics and metabolomics of isogenic mutant vs wild-type lines","pmids":["28368494"],"confidence":"Medium","gaps":["Correlative, did not establish the endocytic step","Single lab"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Placed Kelch13 at PI3P-rich ER tubules/vesicles and linked its mutation to altered PI3P networks and virulence-adhesin (PfEMP1) export.","evidence":"Cryo-immunoEM, colocalization/copurification with PfEMP1, PI3P vesicle quantification and cytoadherence assays in K13 mutants","pmids":["29363540"],"confidence":"Medium","gaps":["Functional significance of PfEMP1 copurification for resistance unresolved","Single lab","Direct vs indirect Kelch13–PI3P relationship not separated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Defined the central cellular mechanism: Kelch13 marks an endocytic compartment mediating hemoglobin uptake, and its dysfunction reduces heme-dependent artemisinin activation.","evidence":"Identification of Kelch13-compartment proteins, genetic inactivation, hemoglobin endocytosis and ring-stage survival assays","pmids":["31896710"],"confidence":"High","gaps":["Precise molecular role of Kelch13 within the endocytic machinery not defined","How mutations mechanistically impair endocytosis unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Refined Kelch13 subcellular localization (ER, Rab vesicles, adjacent to cytostomes) and its dynamic relocalization to the mitochondrion under drug pressure, plus reversal of mutant resistance by wild-type co-expression.","evidence":"Kelch13-specific monoclonal antibodies, epitope-tagged lines, quantitative imaging, immunoprecipitation and RSA","pmids":["32310999"],"confidence":"High","gaps":["Functional meaning of mitochondrial relocalization unclear","Putative interactors from IP not individually validated","Single lab"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Localized Kelch13 to peripheral cytostome-like structures and showed mislocalization phenocopies resistance mutations, establishing partial loss of function as the operative event.","evidence":"GFP tagging, knock-sideways mislocalization, pulse-SILAC turnover and hemoglobin peptidomics","pmids":["31775055"],"confidence":"High","gaps":["Threshold of Kelch13 activity needed for sensitivity not quantified","Mechanistic link between abundance and endocytic rate incomplete"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Documented emergence and causality of specific propeller mutations across geographies (Rwanda R561H; Guyana C580Y/R539T; China-Myanmar F446I/N458Y), and showed resistance can also arise Kelch13-independently.","evidence":"CRISPR editing/reversion across strains with RSA and competition assays; long-term in vitro selection yielding pfk13-wild-type resistance","pmids":["32747827","32394893","32098812","29538461"],"confidence":"High","gaps":["Kelch13-independent resistance mechanisms not molecularly defined","Determinants of geographic mutation preference unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2021,"claim":"Showed the resistance effect and fitness cost of Kelch13 mutations are strongly genetic-background dependent, explaining differential spread of alleles.","evidence":"Gene editing of R561H/C580Y/M579I into African and Southeast Asian backgrounds with RSA and fitness competition","pmids":["34279219"],"confidence":"High","gaps":["Modifier loci that permit low-cost resistance not identified","Molecular basis of background dependence unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"Systems profiling broadened the Kelch13-mutant phenotype to cell-cycle, UPR, trafficking and mitochondrial metabolism, with atovaquone reversing resistance and implicating mitochondrial processes.","evidence":"Quantitative transcriptomics/proteomics/metabolomics on isogenic panel plus atovaquone reversal and RSA","pmids":["33483501"],"confidence":"High","gaps":["Causal chain from Kelch13 to mitochondrial metabolism not established","Whether mitochondrial involvement is direct or downstream unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Defined the cross-resistance spectrum, showing Kelch13 mutations confer resistance to the ozonide OZ277 but not generally to OZ439, informing endoperoxide drug design.","evidence":"RSA with DHA, OZ277 and OZ439 plus competition assays in gene-edited isogenic lines","pmids":["28400526"],"confidence":"High","gaps":["Structural basis for differential ozonide cross-resistance unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Correlated an in vitro delayed-clearance assay with in vivo clearance and Kelch13 genotype, tracing resistance to altered stage-specific drug exposure across the cell cycle.","evidence":"In vitro delayed clearance assay with stage-specific exposure quantification and K13 genotyping","pmids":["25779582"],"confidence":"Medium","gaps":["Correlative link between cell-cycle timing and Kelch13 function not mechanistic","Single lab"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"claim":"Extended causal validation to Bangladeshi backgrounds, showing C580Y/R561H confer strong resistance with minimal fitness cost and, for R561H in a resistant background, a growth advantage.","evidence":"CRISPR-Cas9 editing into two Bangladeshi isolates with RSA, recovery and competitive fitness assays","pmids":["41841738"],"confidence":"Medium","gaps":["Single lab, single study","Mechanism of the R561H growth advantage undefined","Interaction with the K13-independent resistance background unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The precise molecular activity of Kelch13 within the endocytic/vesicular machinery and how propeller mutations mechanistically reduce hemoglobin uptake and integrate PI3P, proteostasis and mitochondrial changes remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of mutant vs wild-type propeller function reconciling all phenotypes","Ubiquitin-ligase and endocytic partners incompletely defined","Unified causal chain linking hemoglobin uptake, PI3P, UPR and mitochondrial metabolism missing"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Kelch13-defined endosomal/vesicular compartment (Kelch13 plus eight compartment proteins whose loss confers artemisinin resistance) [#5]"],"partners":["PFPI3K (BOUND AND TARGETED FOR POLYUBIQUITINATION/PROTEOLYSIS BY KELCH13) [#2]","PFEMP1 (COLOCALIZES AND COPURIFIES WITH KELCH13) [#7]","RAB GTPASES AND ER-RESIDENT AND MITOCHONDRIAL PROTEINS (PUTATIVE KELCH13-ASSOCIATED PROTEINS BY IMMUNOPRECIPITATION) [#6]"],"other_free_text":["Kelch13 propeller-domain mutations (C580Y, R561H, R539T, M579I, F446I, N458Y, I543T among others) are the principal genetic determinant of ring-stage artemisinin resistance and confer cross-resistance to the ozonide OZ277 but generally not OZ439 [#0, #1, #13].","Resistance magnitude and fitness cost of Kelch13 mutations are strongly dependent on parasite genetic background [#11, #18].","Kelch13 mutations reduce Kelch13 protein abundance, decrease hemoglobin endocytosis and digestion, elevate PI3P, and attenuate the proteotoxic stress response; proteasome inhibition synergizes with artemisinin [#3, #8, #2, #12].","Artemisinin resistance can also emerge independently of Kelch13 mutations via enhanced oxidative/proteotoxic stress responses [#15].","Kelch13 is essential across asexual erythrocytic stages and is expressed in gametocytes [#4, #10]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25075834","id":"PMC_25075834","title":"Spread of artemisinin resistance in Plasmodium falciparum malaria.","date":"2014","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25075834","citation_count":1669,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Kelch13"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24352242","id":"PMC_24352242","title":"A molecular marker of 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Using whole-genome sequencing of an artemisinin-resistant parasite line and clinical isolates, mutant K13-propeller alleles were found to cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant allele correlates with the recent spread of resistance in western Cambodia.\",\n      \"method\": \"Whole-genome sequencing of artemisinin-resistant parasite line; in vitro parasite survival assays; in vivo parasite clearance rate measurements in patients\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (WGS, in vitro RSA, in vivo clearance) in a landmark study; independently replicated across many subsequent studies\",\n      \"pmids\": [\"24352242\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Genetic modification of the Kelch13 locus using zinc-finger nucleases demonstrated that K13 mutations are causally sufficient to confer artemisinin resistance. Removal of K13 mutations from resistant Cambodian isolates reduced ring-stage survival rates from 13–49% to 0.3–2.4%, while insertion of K13 mutations into wild-type parasites increased survival rates from ≤0.6% to 2–29%.\",\n      \"method\": \"Zinc-finger nuclease-mediated genetic modification of the Kelch13 locus in P. falciparum; ring-stage survival assay (RSA)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct causal demonstration via reciprocal gene editing (insertion and removal of mutations) with functional phenotypic readout; landmark study independently replicated\",\n      \"pmids\": [\"25502314\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kelch13 (PfKelch13) binds to and promotes polyubiquitination and proteolysis of PfPI3K. The C580Y resistance mutation in Kelch13 reduces polyubiquitination of PfPI3K and its binding to Kelch13, limiting PfPI3K proteolysis and thereby increasing PfPI3K levels and its lipid product phosphatidylinositol-3-phosphate (PI3P). Elevated PI3P was shown to be predictive of artemisinin resistance.\",\n      \"method\": \"Biochemical binding assays; polyubiquitination assays; measurement of PfPI3K protein levels and PI3P lipid levels in resistant clinical strains vs. wild-type; in vitro and in vivo artemisinin susceptibility assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution of binding/ubiquitination, multiple orthogonal methods (protein levels, lipid levels, in vitro/in vivo drug assays), single lab but multiple method types\",\n      \"pmids\": [\"25874676\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kelch13 mutations result in decreased expression of the Kelch13 protein, and mislocalization of Kelch13 (using a knock-sideways approach) mimics resistance-conferring mutations, indicating that partial loss of function of Kelch13 is the relevant molecular event for resistance. Kelch13-GFP localizes to ~170 nm diameter doughnut-shaped structures at the parasite periphery consistent with cytostomes. Mislocalization of Kelch13 reduces the hemoglobin-peptide profile of ring-stage parasites and reduces disruption to protein turnover following artemisinin exposure.\",\n      \"method\": \"Mislocalization (knock-sideways) of Kelch13 using GFP tagging; fluorescence microscopy; pulse-SILAC protein turnover quantification; peptidomics of hemoglobin-derived peptides\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, multiple orthogonal methods (microscopy, proteomics, peptidomics), single lab\",\n      \"pmids\": [\"31775055\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Using selection-linked integration (SLI), Kelch13 was localized and inducibly inactivated in P. falciparum. Inducible inactivation of Kelch13 demonstrated it is an essential protein. The SLI approach allowed functional analysis at gene and protein levels including mislocalization of the native protein.\",\n      \"method\": \"Selection-linked integration (SLI) for genomic integration; knock-sideways mislocalization; DiCre-based conditional gene excision; fluorescence microscopy\",\n      \"journal\": \"Nature methods\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct inactivation/mislocalization experiment with functional readout (essentiality confirmed), single lab, single study\",\n      \"pmids\": [\"28288121\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kelch13 defines a specific endosomal/vesicular compartment in P. falciparum. Inactivation of Kelch13 or expression of a resistance-conferring Kelch13 mutation reduced hemoglobin endocytosis from the host red cell. Since artemisinins are activated by hemoglobin degradation products (heme), reduced hemoglobin endocytosis caused by Kelch13 dysfunction leads to decreased artemisinin activation and parasite resistance. Eight Kelch13-compartment proteins were identified whose inactivation also rendered parasites resistant to artemisinin.\",\n      \"method\": \"Identification of Kelch13-compartment proteins; genetic inactivation of Kelch13 and interactors; hemoglobin endocytosis assays; ring-stage survival assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple proteins tested by genetic inactivation with specific cellular phenotype (hemoglobin endocytosis), resistance-conferring mutation validated, multiple orthogonal methods, independently supported by other studies\",\n      \"pmids\": [\"31896710\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kelch13 localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes (which traffic hemoglobin to the digestive vacuole). Upon treatment with dihydroartemisinin, Kelch13 partially relocalizes near the parasite mitochondria. Immunoprecipitation with Kelch13-specific monoclonal antibodies identified multiple putative Kelch13-associated proteins including ER-resident molecules, mitochondrial proteins, and Rab GTPases. Co-expression of wild-type Kelch13 reversed mutant Kelch13-mediated resistance.\",\n      \"method\": \"K13-specific monoclonal antibodies; gene-edited parasite lines co-expressing epitope-tagged Kelch13; quantitative imaging pipeline; immunoprecipitation; fluorescence microscopy; ring-stage survival assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation with specific antibodies, localization confirmed by multiple orthogonal approaches (antibodies + tagged lines + imaging pipeline), resistance reversal experiment, single lab with multiple methods\",\n      \"pmids\": [\"32310999\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kelch13 concentrates at PI3P tubules/vesicles of the parasite's endoplasmic reticulum in infected red cells. Kelch13 colocalizes and copurifies with the major virulence adhesin PfEMP1. The C580Y resistance mutation quantitatively increased PI3P tubules/vesicles, exporting them throughout the parasite and the red cell. Multiple Kelch13 mutants showed alterations in PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor.\",\n      \"method\": \"Cryoimmunoelectron microscopy; colocalization and copurification experiments; PI3P vesicle quantification; PfEMP1 export and cytoadherence assays in K13 mutant parasites\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cryo-immunoEM localization, copurification evidence, multiple K13 mutant lines tested, single lab\",\n      \"pmids\": [\"29363540\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Multi-omics profiling of PfKelch13-mutant artemisinin-resistant vs. sensitive P. falciparum strains revealed that Kelch13 mutations are specifically associated with decreased abundance of Kelch13 protein itself, decreased hemoglobin digestion (lower abundance of hemoglobin-derived peptides), and enhanced glutathione production.\",\n      \"method\": \"LC-MS-based proteomics, peptidomics, and metabolomics of isogenic Kelch13 mutant and wild-type parasite lines\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal omics methods on isogenic lines, single lab, consistent mechanistic picture\",\n      \"pmids\": [\"28368494\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Systems-based quantitative transcriptomics, proteomics, and metabolomics applied to isogenic Kelch13 mutant and wild-type P. falciparum lines showed that Kelch13 mutations alter multiple aspects of the parasite's intra-erythrocytic developmental program, including cell-cycle periodicity, unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. Kelch13-mediated resistance in the Cambodian Cam3.II line was reversed by atovaquone (a mitochondrial electron transport chain inhibitor), implicating mitochondrial processes in resistance.\",\n      \"method\": \"Isogenic K13 mutant panel; quantitative transcriptomics, proteomics, and metabolomics; atovaquone reversal experiment; ring-stage survival assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal omics on isogenic panel plus functional reversal experiment, single lab, rigorous controls\",\n      \"pmids\": [\"33483501\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PfKelch13 protein is expressed ubiquitously in all asexual erythrocytic stages and in gametocytes, and localizes to punctate structures partially overlapping an endoplasmic reticulum marker. Introduction of four PfKelch13 mutations (F446I, N458Y, C469Y, F495L) from China-Myanmar border parasites into the 3D7 strain showed higher RSA survival rates, with N458Y yielding the most significant increase (26.3%). Reversion of these mutations in field isolates reduced RSA values. F446I caused prolonged ring-stage development with minimal fitness cost.\",\n      \"method\": \"GFP-tagging of PfKelch13; new anti-PfKelch13 antibody; fluorescence microscopy; CRISPR-based mutation introduction and reversion; ring-stage survival assay; in vitro culture competition assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with antibody and GFP tag, mutation introduction and reversion experiments with functional readout, single lab\",\n      \"pmids\": [\"32098812\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Gene editing of multiple Kelch13 mutations (including R561H, C580Y, M579I) into African (3D7) and Southeast Asian (Dd2 and other) P. falciparum strain backgrounds showed that the resistance conferred by Kelch13 mutations depends on genetic background. C580Y and M579I cause substantial fitness costs in most backgrounds but not in recent Cambodian strains; R561H is fitness neutral in African 3D7 parasites. Only R561H yielded ART resistance comparable to C580Y when edited into Southeast Asian strains.\",\n      \"method\": \"Gene editing (introduction of K13 mutations into multiple strain backgrounds); ring-stage survival assay; mixed-culture fitness competition assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic gene editing across multiple strain backgrounds with both resistance and fitness readouts, multiple mutations tested, replication of key findings\",\n      \"pmids\": [\"34279219\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ART treatment induces growth retardation and accumulation of ubiquitinated proteins in wild-type parasites, indicative of a cellular stress response engaging the ubiquitin/proteasome system. Resistant parasites carrying K13 propeller mutations exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. Inhibiting the proteasome strongly synergizes ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type Kelch13.\",\n      \"method\": \"Kinetic analysis of drug responses; measurement of ubiquitinated protein levels; proteasome inhibitor synergy assays in K13 wild-type and mutant isogenic lines; P. berghei in vivo synergy experiments\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ubiquitin levels, cell death kinetics, drug synergy in isogenic lines), cross-validated in vivo in P. berghei, single lab\",\n      \"pmids\": [\"25901609\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kelch13 mutations (C580Y, R539T, I543T) confer cross-resistance to the ozonide OZ277 (arterolane) in addition to dihydroartemisinin. However, OZ439 (artefenomel) retains activity against most K13 mutant parasites (cross-resistance only observed for the rare I543T mutation). K13 mutations showed variable impacts on parasite growth rates depending on the specific mutation and parasite strain, with the prevalent C580Y mutation being fitness neutral in recently culture-adapted Cambodian strains.\",\n      \"method\": \"Ring-stage survival assay (RSA0-3h) with DHA, OZ439, and OZ277; mixed-culture competition experiments with isogenic K13 lines; gene-edited clinical isolates from Cambodia\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic gene-edited lines, multiple drug treatments, reciprocal fitness competition assays, multiple K13 mutations tested\",\n      \"pmids\": [\"28400526\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Gene editing confirmed that the Kelch13 R561H mutation drives artemisinin resistance in vitro in P. falciparum, providing evidence for de novo emergence of Kelch13-mediated artemisinin resistance in Rwanda.\",\n      \"method\": \"Gene editing (introduction of R561H mutation into P. falciparum); ring-stage survival assay\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct causal demonstration via gene editing with functional RSA readout, independently confirmed in multiple follow-up studies\",\n      \"pmids\": [\"32747827\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vitro artemisinin resistance can emerge independently of Kelch13 mutations in P. falciparum, as shown by long-term in vitro selection that induced profound stage-specific resistance with no pfk13 mutations, associated instead with enhanced adaptive responses against oxidative stress and protein damage.\",\n      \"method\": \"Long-term in vitro selection for artemisinin resistance; chemosensitivity assays; transcriptional profiling; whole-genome sequencing\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative finding regarding Kelch13 mechanistically informative: resistance can arise without Kelch13 mutations; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29538461\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vitro emergence of Kelch13 C580Y mutations in Guyana (South America) in parasites with a genetic origin distinct from Southeast Asia was demonstrated. Introducing C580Y or R539T mutations by gene editing into local Guyanese parasites conferred high levels of in vitro artemisinin resistance. In vitro growth competition assays revealed a fitness cost associated with these Kelch13 variants.\",\n      \"method\": \"Genome analysis; gene editing (CRISPR) to introduce C580Y and R539T into local P. falciparum; ring-stage survival assay; in vitro growth competition assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gene editing with functional phenotype and fitness readout, multiple mutations tested, single lab\",\n      \"pmids\": [\"32394893\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vitro artemisinin resistance assay (delayed clearance assay/DCA) results correlated with parasite clearance half-life in vivo and with mutations in the Kelch13 domain gene (Pf3D7_1343700). Artemisinin-resistant P. falciparum parasites exhibited altered patterns of development resulting in reduced exposure to drug at the trophozoite stage and increased exposure in the ring stage, indicating an altered cell cycle mechanism for resistance.\",\n      \"method\": \"In vitro delayed clearance assay (DCA); stage-specific drug exposure quantification; correlation with in vivo clearance half-life; K13 genotyping\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assay correlated with in vivo phenotype and Kelch13 genotype, multiple isolates, single lab\",\n      \"pmids\": [\"25779582\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Introduction of globally dominant Kelch13 mutations (C580Y, R561H, F446I) by CRISPR-Cas9 into two Bangladeshi P. falciparum isolates (including a K13-independent resistant strain) demonstrated that C580Y and R561H confer marked increases in artemisinin resistance in both backgrounds, while F446I had only modest effects. R561H in the resistant background conferred extreme resistance (RSA 30.09%) and an asexual growth advantage. All three mutations incurred minimal fitness costs in the artemisinin-sensitive background.\",\n      \"method\": \"CRISPR-Cas9 gene editing; ring-stage survival assay; post-treatment recovery assays; competitive fitness assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct gene editing with functional RSA and fitness readouts, two parasite backgrounds tested, single lab, single study\",\n      \"pmids\": [\"41841738\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"Kelch13 (PF3D7_1343700) is a BTB/POZ and kelch-propeller domain protein that localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes; it functions as a regulator of hemoglobin endocytosis (via the cytostome pathway) and promotes polyubiquitination and proteolysis of PfPI3K, thereby controlling PI3P levels and cellular proteostasis — resistance-conferring mutations in its propeller domain reduce Kelch13 protein abundance and function, leading to decreased hemoglobin uptake and heme-mediated artemisinin activation, attenuated proteotoxic stress responses, and elevated PI3P, collectively enabling ring-stage parasites to survive artemisinin exposure.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Kelch13 (PF3D7_1343700) is an essential BTB/POZ- and kelch-propeller-domain protein of Plasmodium falciparum that governs hemoglobin endocytosis and cellular proteostasis, and whose propeller-domain mutations are the principal genetic determinant of artemisinin resistance [#0, #1, #5]. Reciprocal gene editing across multiple parasite backgrounds established that propeller-domain mutations (e.g. C580Y, R561H, R539T, M579I) are causally sufficient to confer ring-stage artemisinin survival, that their effect and fitness cost depend on genetic background, and that these alleles have emerged independently in Southeast Asia, Africa (Rwanda) and South America (Guyana) [#1, #11, #14, #16]. Mechanistically, Kelch13 defines an endosomal/vesicular compartment where it drives hemoglobin uptake from the host red cell via the cytostome pathway; because artemisinins are activated by hemoglobin-derived heme, mutation- or mislocalization-induced loss of Kelch13 function reduces hemoglobin endocytosis and thereby lowers drug activation, and this partial loss of function is accompanied by reduced Kelch13 protein abundance [#3, #5, #8]. Kelch13 also binds PfPI3K and promotes its polyubiquitination and proteolysis, so that resistance mutations elevate PfPI3K and its lipid product PI3P, a change predictive of resistance and associated with altered PI3P vesicle/tubule networks and PfEMP1 export [#2, #7]. Consistent with a proteostasis role, artemisinin engages the ubiquitin/proteasome stress response, Kelch13-mutant parasites mount an attenuated proteotoxic response, and proteasome inhibition synergizes with artemisinin [#12]; systems-level analyses link Kelch13 mutations to altered cell-cycle periodicity, the unfolded protein response, vesicular trafficking and mitochondrial metabolism [#9]. Kelch13 localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes, and relocalizes toward the mitochondrion upon dihydroartemisinin exposure [#3, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the first genetic marker of artemisinin resistance by linking a specific parasite locus to the clinical phenotype, previously defined only by delayed parasite clearance.\",\n      \"evidence\": \"Whole-genome sequencing of a resistant line plus in vitro survival and in vivo clearance measurements in Cambodian isolates\",\n      \"pmids\": [\"24352242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Association only \\u2014 did not prove causality\", \"No molecular function assigned to Kelch13\", \"Mechanism of resistance unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Proved that Kelch13 propeller mutations are causally sufficient for resistance, moving the field from correlation to causation.\",\n      \"evidence\": \"Zinc-finger nuclease reciprocal editing (insertion and removal of mutations) with ring-stage survival readout\",\n      \"pmids\": [\"25502314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical function of Kelch13\", \"Did not identify how mutations alter protein activity\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided a biochemical mechanism by identifying PfPI3K as a Kelch13 target whose ubiquitin-dependent turnover controls PI3P, and mutations relieve this control.\",\n      \"evidence\": \"Binding and polyubiquitination assays plus PfPI3K/PI3P quantification in resistant strains and drug susceptibility assays\",\n      \"pmids\": [\"25874676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase machinery not fully defined\", \"Relationship between PI3P elevation and hemoglobin/heme pathway not integrated\", \"Single lab for the biochemical reconstitution\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected resistance to an attenuated proteotoxic stress response and revealed a therapeutic vulnerability via proteasome inhibition.\",\n      \"evidence\": \"Ubiquitinated-protein and cell-death kinetics plus proteasome-inhibitor synergy in isogenic lines, cross-validated in vivo in P. berghei\",\n      \"pmids\": [\"25901609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly link Kelch13 to proteasome regulation mechanistically\", \"Which stress-response components are Kelch13-dependent unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed Kelch13 essentiality and enabled functional dissection via inducible inactivation and mislocalization of the native protein.\",\n      \"evidence\": \"Selection-linked integration with DiCre excision and knock-sideways mislocalization plus microscopy\",\n      \"pmids\": [\"28288121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single study\", \"Did not resolve the essential molecular activity\", \"Essentiality vs. partial-loss-of-function distinction for resistance not addressed here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multi-omics tied Kelch13 mutations to reduced Kelch13 protein, decreased hemoglobin digestion, and altered redox metabolism, foreshadowing the hemoglobin-uptake mechanism.\",\n      \"evidence\": \"LC-MS proteomics, peptidomics and metabolomics of isogenic mutant vs wild-type lines\",\n      \"pmids\": [\"28368494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative, did not establish the endocytic step\", \"Single lab\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed Kelch13 at PI3P-rich ER tubules/vesicles and linked its mutation to altered PI3P networks and virulence-adhesin (PfEMP1) export.\",\n      \"evidence\": \"Cryo-immunoEM, colocalization/copurification with PfEMP1, PI3P vesicle quantification and cytoadherence assays in K13 mutants\",\n      \"pmids\": [\"29363540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of PfEMP1 copurification for resistance unresolved\", \"Single lab\", \"Direct vs indirect Kelch13\\u2013PI3P relationship not separated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the central cellular mechanism: Kelch13 marks an endocytic compartment mediating hemoglobin uptake, and its dysfunction reduces heme-dependent artemisinin activation.\",\n      \"evidence\": \"Identification of Kelch13-compartment proteins, genetic inactivation, hemoglobin endocytosis and ring-stage survival assays\",\n      \"pmids\": [\"31896710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise molecular role of Kelch13 within the endocytic machinery not defined\", \"How mutations mechanistically impair endocytosis unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined Kelch13 subcellular localization (ER, Rab vesicles, adjacent to cytostomes) and its dynamic relocalization to the mitochondrion under drug pressure, plus reversal of mutant resistance by wild-type co-expression.\",\n      \"evidence\": \"Kelch13-specific monoclonal antibodies, epitope-tagged lines, quantitative imaging, immunoprecipitation and RSA\",\n      \"pmids\": [\"32310999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional meaning of mitochondrial relocalization unclear\", \"Putative interactors from IP not individually validated\", \"Single lab\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localized Kelch13 to peripheral cytostome-like structures and showed mislocalization phenocopies resistance mutations, establishing partial loss of function as the operative event.\",\n      \"evidence\": \"GFP tagging, knock-sideways mislocalization, pulse-SILAC turnover and hemoglobin peptidomics\",\n      \"pmids\": [\"31775055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold of Kelch13 activity needed for sensitivity not quantified\", \"Mechanistic link between abundance and endocytic rate incomplete\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Documented emergence and causality of specific propeller mutations across geographies (Rwanda R561H; Guyana C580Y/R539T; China-Myanmar F446I/N458Y), and showed resistance can also arise Kelch13-independently.\",\n      \"evidence\": \"CRISPR editing/reversion across strains with RSA and competition assays; long-term in vitro selection yielding pfk13-wild-type resistance\",\n      \"pmids\": [\"32747827\", \"32394893\", \"32098812\", \"29538461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kelch13-independent resistance mechanisms not molecularly defined\", \"Determinants of geographic mutation preference unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed the resistance effect and fitness cost of Kelch13 mutations are strongly genetic-background dependent, explaining differential spread of alleles.\",\n      \"evidence\": \"Gene editing of R561H/C580Y/M579I into African and Southeast Asian backgrounds with RSA and fitness competition\",\n      \"pmids\": [\"34279219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Modifier loci that permit low-cost resistance not identified\", \"Molecular basis of background dependence unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Systems profiling broadened the Kelch13-mutant phenotype to cell-cycle, UPR, trafficking and mitochondrial metabolism, with atovaquone reversing resistance and implicating mitochondrial processes.\",\n      \"evidence\": \"Quantitative transcriptomics/proteomics/metabolomics on isogenic panel plus atovaquone reversal and RSA\",\n      \"pmids\": [\"33483501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from Kelch13 to mitochondrial metabolism not established\", \"Whether mitochondrial involvement is direct or downstream unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the cross-resistance spectrum, showing Kelch13 mutations confer resistance to the ozonide OZ277 but not generally to OZ439, informing endoperoxide drug design.\",\n      \"evidence\": \"RSA with DHA, OZ277 and OZ439 plus competition assays in gene-edited isogenic lines\",\n      \"pmids\": [\"28400526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential ozonide cross-resistance unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Correlated an in vitro delayed-clearance assay with in vivo clearance and Kelch13 genotype, tracing resistance to altered stage-specific drug exposure across the cell cycle.\",\n      \"evidence\": \"In vitro delayed clearance assay with stage-specific exposure quantification and K13 genotyping\",\n      \"pmids\": [\"25779582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative link between cell-cycle timing and Kelch13 function not mechanistic\", \"Single lab\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended causal validation to Bangladeshi backgrounds, showing C580Y/R561H confer strong resistance with minimal fitness cost and, for R561H in a resistant background, a growth advantage.\",\n      \"evidence\": \"CRISPR-Cas9 editing into two Bangladeshi isolates with RSA, recovery and competitive fitness assays\",\n      \"pmids\": [\"41841738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single study\", \"Mechanism of the R561H growth advantage undefined\", \"Interaction with the K13-independent resistance background unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise molecular activity of Kelch13 within the endocytic/vesicular machinery and how propeller mutations mechanistically reduce hemoglobin uptake and integrate PI3P, proteostasis and mitochondrial changes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of mutant vs wild-type propeller function reconciling all phenotypes\", \"Ubiquitin-ligase and endocytic partners incompletely defined\", \"Unified causal chain linking hemoglobin uptake, PI3P, UPR and mitochondrial metabolism missing\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031625\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0043130\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [2, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 6, 7, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6, 5]},\n      {\"term_id\": \"GO:0020020\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006897\", \"supporting_discovery_ids\": [5, 3]},\n      {\"term_id\": \"GO:0006511\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0030163\", \"supporting_discovery_ids\": [3, 9, 12]},\n      {\"term_id\": \"GO:0016192\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0046488\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"complexes\": [\n      \"Kelch13-defined endosomal/vesicular compartment (Kelch13 plus eight compartment proteins whose loss confers artemisinin resistance) [#5]\"\n    ],\n    \"partners\": [\n      \"PfPI3K (bound and targeted for polyubiquitination/proteolysis by Kelch13) [#2]\",\n      \"PfEMP1 (colocalizes and copurifies with Kelch13) [#7]\",\n      \"Rab GTPases and ER-resident and mitochondrial proteins (putative Kelch13-associated proteins by immunoprecipitation) [#6]\"\n    ],\n    \"other_free_text\": [\n      \"Kelch13 propeller-domain mutations (C580Y, R561H, R539T, M579I, F446I, N458Y, I543T among others) are the principal genetic determinant of ring-stage artemisinin resistance and confer cross-resistance to the ozonide OZ277 but generally not OZ439 [#0, #1, #13].\",\n      \"Resistance magnitude and fitness cost of Kelch13 mutations are strongly dependent on parasite genetic background [#11, #18].\",\n      \"Kelch13 mutations reduce Kelch13 protein abundance, decrease hemoglobin endocytosis and digestion, elevate PI3P, and attenuate the proteotoxic stress response; proteasome inhibition synergizes with artemisinin [#3, #8, #2, #12].\",\n      \"Artemisinin resistance can also emerge independently of Kelch13 mutations via enhanced oxidative/proteotoxic stress responses [#15].\",\n      \"Kelch13 is essential across asexual erythrocytic stages and is expressed in gametocytes [#4, #10].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1343700","name":null,"product":"kelch protein K13","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1356700","name":null,"product":"kelch protein K13, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1257700","name":null,"product":"kelch protein K13, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"Kelch13","evaluation":null}