{"gene":"PF3D7_1302200","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2004,"finding":"UIS3 is essential for early liver-stage development: uis3-deficient P. berghei sporozoites infect hepatocytes but are unable to establish blood-stage infections in vivo, demonstrating a specific developmental block during intrahepatic parasite development.","method":"Reverse genetics / targeted gene knockout in Plasmodium berghei; in vivo rodent malaria infection model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined in vivo phenotype, replicated across multiple subsequent labs","pmids":["15580261"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2007,"finding":"UIS3 (as PVM-localized protein) interacts directly with host liver fatty acid-binding protein (L-FABP) in hepatocytes, and knockdown of L-FABP impairs parasite growth while L-FABP overexpression promotes growth, identifying a host-parasite molecular interaction important for liver-stage development.","method":"Yeast two-hybrid screen; yeast overexpression system; L-FABP knockdown and overexpression in hepatocytes with parasite growth readout","journal":"International journal for parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional overexpression/knockdown, single lab, two orthogonal methods; but later NMR study (PMID 23169100) challenges the direct interaction","pmids":["17303141"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium yoelii","strain":""}]},{"year":2007,"finding":"Deletion of UIS3 in P. yoelii generates genetically attenuated parasites (Pyuis3[-]) that reach the liver, invade hepatocytes, form a parasitophorous vacuole, but do not significantly persist beyond 40 hours post-infection, defining the developmental arrest point.","method":"Targeted gene deletion in P. yoelii; in vivo quantification of liver parasite persistence by qRT-PCR and blood-stage monitoring","journal":"The Journal of infectious diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype and time-course quantification, replicated across species","pmids":["17624848"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2008,"finding":"UIS3 protein is localized to the parasitophorous vacuolar membrane (PVM) in infected hepatocytes, consistent with its role at the parasite-host interface.","method":"Crystal structure determination; biochemical localization data reported alongside structural analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure of P. falciparum UIS3 soluble domain at 2.5 Å resolution, single lab with structural and biochemical validation","pmids":["18577521"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"The crystal structure of the soluble domain of P. falciparum UIS3 (PfUIS3 residues 130–229) at 2.5 Å resolution reveals a novel all-alpha-helical fold bound to one molecule of phosphatidylethanolamine (PE), with a defined lipid-binding site where the PE head group makes specific contacts and one acyl chain docks into a hydrophobic channel.","method":"X-ray crystallography at 2.5 Å resolution; biochemical lipid-binding assays with phospholipid liposomes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure with biochemical validation of lipid binding, single lab but rigorous structural method","pmids":["18577521"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"The PfUIS3 soluble domain (residues 130–229) interacts with human liver fatty acid-binding protein (L-FABP) in biochemical assays, consistent with a role in fatty acid/lipid import into the parasite.","method":"Biochemical interaction assays (co-incubation with L-FABP); structural analysis","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single biochemical assay in a structural paper, and contradicted by subsequent NMR study (PMID 23169100)","pmids":["18577521"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"SAP1 deletion in P. yoelii abolishes expression of UIS3 (along with UIS4 and P52) in sporozoites, while constitutively expressed genes (CSP, TRAP) are unaffected, placing UIS3 downstream of SAP1 in a post-transcriptional regulatory pathway controlling infectivity genes.","method":"Targeted deletion of SAP1 in P. yoelii; RT-PCR and protein expression analysis of UIS3 and other genes in sap1(-) parasites","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by clean knockout with specific gene expression readout, single lab","pmids":["18466298"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2013,"finding":"NMR spectroscopy shows no direct interaction between the soluble domain of P. falciparum UIS3 and human L-FABP (in either unbound or oleate-loaded form), and the UIS3 spectrum is unchanged upon addition of oleate or phospholipids, challenging the model of direct lipid transfer from L-FABP to UIS3.","method":"Solution NMR spectroscopy (1H,15N-2D HSQC); amino acid residue-specific interaction analysis","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution NMR with residue-level analysis is rigorous, but single lab reporting a negative result that contradicts prior work","pmids":["23169100"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"The PVM transmembrane protein UIS3 of P. berghei binds host LC3 (microtubule-associated protein 1 light chain 3) through a non-canonical interaction with a specialized surface on LC3 that is also used by host LC3-interacting proteins with essential autophagy functions, thereby competitively inhibiting autophagy-mediated elimination of the parasite from hepatocytes.","method":"Protein-protein interaction assays (co-IP, pulldown); competition assays with LC3-interacting host proteins; parasite survival assays in autophagy-proficient vs. deficient hepatocytes; genetic loss-of-function with uis3(-) parasites","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction assays, competition binding, genetic KO with cellular phenotype, multiple orthogonal methods across labs","pmids":["29109477"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2020,"finding":"Disruption of the UIS3–LC3 protein-protein interaction by a small molecule (C4) triggers parasite elimination from hepatocytes in an autophagy-dependent manner, confirming that UIS3 binding to LC3 is mechanistically required for autophagy evasion during liver-stage infection.","method":"Molecular docking screen of >20 million compounds; phenotypic infection screen; biophysical assays to confirm C4 disrupts UIS3–LC3 interaction; parasite infection assays in autophagy-sufficient vs. deficient cells","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — small-molecule disruption of a specific interaction validated by biophysical assay plus functional autophagy-dependent phenotype, multiple orthogonal methods","pmids":["33214643"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"finding":"uis3(-) P. berghei parasites are restricted by host GABARAPs (another Atg8 subfamily) independently of canonical autophagy, while cells lacking LC3 proteins still restrict uis3(-) parasite growth; cells lacking Atg9 or Atg14 (essential for autophagy) do not relieve restriction of uis3(-) parasites, demonstrating that the relevant host pathway suppressing uis3(-) parasite growth is GABARAP-dependent but autophagy-independent.","method":"Genetic loss-of-function in host cells (Atg3, Atg5, Atg7, Atg9, Atg14, LC3, GABARAP knockouts); uis3(-) P. berghei parasite infection assays with quantification of parasite growth","journal":"Parasitology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in multiple host KO lines with quantified parasite growth, single lab but multiple genetic perturbations","pmids":["33771680"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"UIS3 (PF3D7_1302200) is a Plasmodium parasitophorous vacuole membrane (PVM) transmembrane protein, essential for early liver-stage development, whose soluble domain adopts an all-alpha-helical fold that binds phosphatidylethanolamine; during hepatocyte infection, UIS3 sequesters host LC3 through a non-canonical competitive interaction to block autophagy-mediated parasite elimination, a function suppressible by small-molecule disruption of the UIS3–LC3 interface, while host GABARAPs (not LC3 or canonical autophagy) mediate the cell-autonomous restriction seen when UIS3 is absent."},"narrative":{"mechanistic_narrative":"UIS3 (PF3D7_1302200) is a Plasmodium parasitophorous vacuolar membrane (PVM) protein that is essential for early liver-stage development, acting at the parasite-host interface to permit intrahepatic survival and progression to blood-stage infection [PMID:15580261, PMID:18577521]. Genetic ablation of UIS3 does not block hepatocyte invasion or parasitophorous vacuole formation but arrests development shortly thereafter, with P. yoelii uis3(-) parasites failing to persist beyond ~40 hours post-infection [PMID:17624848]. Its expression is controlled post-transcriptionally, being abolished in sporozoites lacking SAP1, placing UIS3 downstream of SAP1 in a regulatory pathway for infectivity genes [PMID:18466298]. The soluble domain of P. falciparum UIS3 adopts a novel all-alpha-helical fold with a defined lipid-binding site that engages one molecule of phosphatidylethanolamine [PMID:18577521]. Mechanistically, the P. berghei PVM protein UIS3 binds host LC3 through a non-canonical interaction with the surface LC3 normally uses for its LC3-interacting partners, thereby competitively blocking autophagy-mediated elimination of the parasite; small-molecule disruption of the UIS3-LC3 interface triggers autophagy-dependent parasite clearance [PMID:29109477, PMID:33214643]. In the absence of UIS3, cell-autonomous restriction of P. berghei is mediated by host GABARAPs independently of canonical autophagy rather than by LC3 [PMID:33771680]. An early model of UIS3 as a direct lipid-transfer partner of host liver fatty acid-binding protein (L-FABP) is not supported: NMR analysis detected no direct interaction between the UIS3 soluble domain and L-FABP [PMID:23169100].","teleology":[{"year":2004,"claim":"Establishing whether UIS3 has a non-redundant role in the parasite life cycle, the first knockout defined it as specifically required for the transition through the liver stage.","evidence":"Targeted gene knockout in P. berghei with in vivo rodent infection readout","pmids":["15580261"],"confidence":"High","gaps":["Does not identify the molecular activity of UIS3","Does not localize the protein or define the arrest step"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2007,"claim":"To pinpoint where in liver-stage development UIS3 is required, deletion in a second species mapped the arrest to a post-invasion step after vacuole formation.","evidence":"Targeted gene deletion in P. yoelii with time-course quantification of liver parasite persistence","pmids":["17624848"],"confidence":"High","gaps":["Does not explain the molecular cause of the ~40 h arrest","Does not connect the arrest to a specific host pathway"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2007,"claim":"Seeking a host binding partner to explain the liver-stage dependency, a screen proposed UIS3 engagement of host L-FABP as a route for lipid acquisition.","evidence":"Yeast two-hybrid plus L-FABP knockdown/overexpression with parasite growth readout in hepatocytes (P. falciparum, P. yoelii)","pmids":["17303141"],"confidence":"Medium","gaps":["Direct UIS3-L-FABP binding later not confirmed by NMR (#7)","L-FABP growth effect not shown to require the UIS3 interaction specifically"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium yoelii","strain":""}]},{"year":2008,"claim":"To place UIS3 in the regulatory hierarchy governing sporozoite infectivity, epistasis showed its expression depends on SAP1.","evidence":"SAP1 deletion in P. yoelii with RT-PCR and protein expression analysis of UIS3","pmids":["18466298"],"confidence":"Medium","gaps":["Does not resolve whether regulation is transcriptional stability or translational","Does not establish a direct SAP1-UIS3 molecular link"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2008,"claim":"Defining UIS3 at atomic resolution revealed a novel all-alpha-helical fold with a lipid-binding pocket occupied by phosphatidylethanolamine, giving the first structural basis for a biochemical function.","evidence":"X-ray crystallography of the PfUIS3 soluble domain at 2.5 A with liposome lipid-binding assays; PVM localization reported alongside","pmids":["18577521"],"confidence":"High","gaps":["Physiological role of PE binding in liver-stage development not established","Structure covers only the soluble domain, not the transmembrane context"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Testing the proposed lipid-transfer model, NMR found no direct UIS3-L-FABP interaction, revising the earlier host-partner hypothesis.","evidence":"Solution NMR (1H,15N HSQC) with residue-level interaction analysis of PfUIS3 soluble domain and L-FABP","pmids":["23169100"],"confidence":"Medium","gaps":["Single-lab negative result","Does not exclude an indirect or full-length/membrane-dependent interaction"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Explaining how the parasite evades host defense, UIS3 was shown to bind host LC3 non-canonically and competitively block autophagy-mediated parasite elimination.","evidence":"Co-IP/pulldown, competition binding with LC3-interacting proteins, and uis3(-) survival assays in autophagy-proficient vs -deficient hepatocytes (P. berghei)","pmids":["29109477"],"confidence":"High","gaps":["Structural basis of the non-canonical LC3 interface not fully resolved","Does not distinguish LC3 from other Atg8 subfamily members as the operative restriction factor"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2020,"claim":"To prove causality and test druggability of the evasion mechanism, small-molecule disruption of the UIS3-LC3 interface triggered autophagy-dependent parasite clearance.","evidence":"Docking screen, biophysical confirmation of C4-mediated disruption, and infection assays in autophagy-sufficient vs -deficient cells (P. berghei)","pmids":["33214643"],"confidence":"High","gaps":["In vivo efficacy and selectivity of C4 not established","Does not address the GABARAP-dependent restriction arm"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"claim":"Resolving which host pathway restricts UIS3-deficient parasites, genetic dissection showed restriction is GABARAP-dependent but autophagy- and LC3-independent, refining the evasion model.","evidence":"Panel of host autophagy-gene and Atg8-family knockouts with uis3(-) P. berghei growth quantification","pmids":["33771680"],"confidence":"Medium","gaps":["Molecular mechanism of GABARAP-mediated restriction not defined","Whether UIS3 itself engages GABARAPs is not established"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"It remains unresolved how UIS3's PE-binding activity and PVM residence mechanistically connect to its host LC3/GABARAP-directed immune evasion function, and whether these represent one integrated activity or separable roles.","evidence":"No timeline discovery links the lipid-binding pocket to the LC3-binding/autophagy-evasion function","pmids":[],"confidence":"Low","gaps":["No structure of UIS3 bound to LC3","Role of PE binding in vivo unknown","Whether UIS3 directly engages GABARAPs is untested"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["HOST LC3 / MAP1LC3 [#8]","HOST GABARAP (RESTRICTION OF UIS3(-) PARASITES, AUTOPHAGY-INDEPENDENT) [#10]","PHOSPHATIDYLETHANOLAMINE (BOUND LIGAND) [#4]","HOST L-FABP (PROPOSED BY Y2H/BIOCHEMICAL ASSAY [#1, #5]; DIRECT BINDING NOT DETECTED BY NMR [#7])"],"other_free_text":["Essential for early liver-stage development; uis3(-) parasites invade hepatocytes and form a parasitophorous vacuole but arrest by ~40 h post-infection and fail to establish blood-stage infection [#0, #2].","Expression is post-transcriptionally dependent on SAP1 in sporozoites [#6].","Soluble domain adopts a novel all-alpha-helical fold with a defined lipid-binding site [#4].","Small molecule C4 disrupts the UIS3-LC3 interface and triggers autophagy-dependent parasite elimination [#9]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"15580261","id":"PMC_15580261","title":"Genetically modified Plasmodium parasites as a protective experimental malaria 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41599054","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["UIS3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13469,"output_tokens":2977,"usd":0.042531,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8713,"output_tokens":3750,"usd":0.068657,"stage2_stop_reason":"end_turn"},"total_usd":0.111188,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"UIS3 is essential for early liver-stage development: uis3-deficient P. berghei sporozoites infect hepatocytes but are unable to establish blood-stage infections in vivo, demonstrating a specific developmental block during intrahepatic parasite development.\",\n      \"method\": \"Reverse genetics / targeted gene knockout in Plasmodium berghei; in vivo rodent malaria infection model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined in vivo phenotype, replicated across multiple subsequent labs\",\n      \"pmids\": [\"15580261\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UIS3 (as PVM-localized protein) interacts directly with host liver fatty acid-binding protein (L-FABP) in hepatocytes, and knockdown of L-FABP impairs parasite growth while L-FABP overexpression promotes growth, identifying a host-parasite molecular interaction important for liver-stage development.\",\n      \"method\": \"Yeast two-hybrid screen; yeast overexpression system; L-FABP knockdown and overexpression in hepatocytes with parasite growth readout\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional overexpression/knockdown, single lab, two orthogonal methods; but later NMR study (PMID 23169100) challenges the direct interaction\",\n      \"pmids\": [\"17303141\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Deletion of UIS3 in P. yoelii generates genetically attenuated parasites (Pyuis3[-]) that reach the liver, invade hepatocytes, form a parasitophorous vacuole, but do not significantly persist beyond 40 hours post-infection, defining the developmental arrest point.\",\n      \"method\": \"Targeted gene deletion in P. yoelii; in vivo quantification of liver parasite persistence by qRT-PCR and blood-stage monitoring\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype and time-course quantification, replicated across species\",\n      \"pmids\": [\"17624848\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UIS3 protein is localized to the parasitophorous vacuolar membrane (PVM) in infected hepatocytes, consistent with its role at the parasite-host interface.\",\n      \"method\": \"Crystal structure determination; biochemical localization data reported alongside structural analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of P. falciparum UIS3 soluble domain at 2.5 Å resolution, single lab with structural and biochemical validation\",\n      \"pmids\": [\"18577521\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The crystal structure of the soluble domain of P. falciparum UIS3 (PfUIS3 residues 130–229) at 2.5 Å resolution reveals a novel all-alpha-helical fold bound to one molecule of phosphatidylethanolamine (PE), with a defined lipid-binding site where the PE head group makes specific contacts and one acyl chain docks into a hydrophobic channel.\",\n      \"method\": \"X-ray crystallography at 2.5 Å resolution; biochemical lipid-binding assays with phospholipid liposomes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure with biochemical validation of lipid binding, single lab but rigorous structural method\",\n      \"pmids\": [\"18577521\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The PfUIS3 soluble domain (residues 130–229) interacts with human liver fatty acid-binding protein (L-FABP) in biochemical assays, consistent with a role in fatty acid/lipid import into the parasite.\",\n      \"method\": \"Biochemical interaction assays (co-incubation with L-FABP); structural analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single biochemical assay in a structural paper, and contradicted by subsequent NMR study (PMID 23169100)\",\n      \"pmids\": [\"18577521\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SAP1 deletion in P. yoelii abolishes expression of UIS3 (along with UIS4 and P52) in sporozoites, while constitutively expressed genes (CSP, TRAP) are unaffected, placing UIS3 downstream of SAP1 in a post-transcriptional regulatory pathway controlling infectivity genes.\",\n      \"method\": \"Targeted deletion of SAP1 in P. yoelii; RT-PCR and protein expression analysis of UIS3 and other genes in sap1(-) parasites\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by clean knockout with specific gene expression readout, single lab\",\n      \"pmids\": [\"18466298\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NMR spectroscopy shows no direct interaction between the soluble domain of P. falciparum UIS3 and human L-FABP (in either unbound or oleate-loaded form), and the UIS3 spectrum is unchanged upon addition of oleate or phospholipids, challenging the model of direct lipid transfer from L-FABP to UIS3.\",\n      \"method\": \"Solution NMR spectroscopy (1H,15N-2D HSQC); amino acid residue-specific interaction analysis\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution NMR with residue-level analysis is rigorous, but single lab reporting a negative result that contradicts prior work\",\n      \"pmids\": [\"23169100\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The PVM transmembrane protein UIS3 of P. berghei binds host LC3 (microtubule-associated protein 1 light chain 3) through a non-canonical interaction with a specialized surface on LC3 that is also used by host LC3-interacting proteins with essential autophagy functions, thereby competitively inhibiting autophagy-mediated elimination of the parasite from hepatocytes.\",\n      \"method\": \"Protein-protein interaction assays (co-IP, pulldown); competition assays with LC3-interacting host proteins; parasite survival assays in autophagy-proficient vs. deficient hepatocytes; genetic loss-of-function with uis3(-) parasites\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction assays, competition binding, genetic KO with cellular phenotype, multiple orthogonal methods across labs\",\n      \"pmids\": [\"29109477\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Disruption of the UIS3–LC3 protein-protein interaction by a small molecule (C4) triggers parasite elimination from hepatocytes in an autophagy-dependent manner, confirming that UIS3 binding to LC3 is mechanistically required for autophagy evasion during liver-stage infection.\",\n      \"method\": \"Molecular docking screen of >20 million compounds; phenotypic infection screen; biophysical assays to confirm C4 disrupts UIS3–LC3 interaction; parasite infection assays in autophagy-sufficient vs. deficient cells\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — small-molecule disruption of a specific interaction validated by biophysical assay plus functional autophagy-dependent phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"33214643\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"uis3(-) P. berghei parasites are restricted by host GABARAPs (another Atg8 subfamily) independently of canonical autophagy, while cells lacking LC3 proteins still restrict uis3(-) parasite growth; cells lacking Atg9 or Atg14 (essential for autophagy) do not relieve restriction of uis3(-) parasites, demonstrating that the relevant host pathway suppressing uis3(-) parasite growth is GABARAP-dependent but autophagy-independent.\",\n      \"method\": \"Genetic loss-of-function in host cells (Atg3, Atg5, Atg7, Atg9, Atg14, LC3, GABARAP knockouts); uis3(-) P. berghei parasite infection assays with quantification of parasite growth\",\n      \"journal\": \"Parasitology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in multiple host KO lines with quantified parasite growth, single lab but multiple genetic perturbations\",\n      \"pmids\": [\"33771680\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"UIS3 (PF3D7_1302200) is a Plasmodium parasitophorous vacuole membrane (PVM) transmembrane protein, essential for early liver-stage development, whose soluble domain adopts an all-alpha-helical fold that binds phosphatidylethanolamine; during hepatocyte infection, UIS3 sequesters host LC3 through a non-canonical competitive interaction to block autophagy-mediated parasite elimination, a function suppressible by small-molecule disruption of the UIS3–LC3 interface, while host GABARAPs (not LC3 or canonical autophagy) mediate the cell-autonomous restriction seen when UIS3 is absent.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UIS3 (PF3D7_1302200) is a Plasmodium parasitophorous vacuolar membrane (PVM) protein that is essential for early liver-stage development, acting at the parasite-host interface to permit intrahepatic survival and progression to blood-stage infection [#0, #3]. Genetic ablation of UIS3 does not block hepatocyte invasion or parasitophorous vacuole formation but arrests development shortly thereafter, with P. yoelii uis3(-) parasites failing to persist beyond ~40 hours post-infection [#2]. Its expression is controlled post-transcriptionally, being abolished in sporozoites lacking SAP1, placing UIS3 downstream of SAP1 in a regulatory pathway for infectivity genes [#6]. The soluble domain of P. falciparum UIS3 adopts a novel all-alpha-helical fold with a defined lipid-binding site that engages one molecule of phosphatidylethanolamine [#4]. Mechanistically, the P. berghei PVM protein UIS3 binds host LC3 through a non-canonical interaction with the surface LC3 normally uses for its LC3-interacting partners, thereby competitively blocking autophagy-mediated elimination of the parasite; small-molecule disruption of the UIS3-LC3 interface triggers autophagy-dependent parasite clearance [#8, #9]. In the absence of UIS3, cell-autonomous restriction of P. berghei is mediated by host GABARAPs independently of canonical autophagy rather than by LC3 [#10]. An early model of UIS3 as a direct lipid-transfer partner of host liver fatty acid-binding protein (L-FABP) is not supported: NMR analysis detected no direct interaction between the UIS3 soluble domain and L-FABP [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing whether UIS3 has a non-redundant role in the parasite life cycle, the first knockout defined it as specifically required for the transition through the liver stage.\",\n      \"evidence\": \"Targeted gene knockout in P. berghei with in vivo rodent infection readout\",\n      \"pmids\": [\"15580261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the molecular activity of UIS3\", \"Does not localize the protein or define the arrest step\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"To pinpoint where in liver-stage development UIS3 is required, deletion in a second species mapped the arrest to a post-invasion step after vacuole formation.\",\n      \"evidence\": \"Targeted gene deletion in P. yoelii with time-course quantification of liver parasite persistence\",\n      \"pmids\": [\"17624848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain the molecular cause of the ~40 h arrest\", \"Does not connect the arrest to a specific host pathway\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Seeking a host binding partner to explain the liver-stage dependency, a screen proposed UIS3 engagement of host L-FABP as a route for lipid acquisition.\",\n      \"evidence\": \"Yeast two-hybrid plus L-FABP knockdown/overexpression with parasite growth readout in hepatocytes (P. falciparum, P. yoelii)\",\n      \"pmids\": [\"17303141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct UIS3-L-FABP binding later not confirmed by NMR (#7)\", \"L-FABP growth effect not shown to require the UIS3 interaction specifically\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"To place UIS3 in the regulatory hierarchy governing sporozoite infectivity, epistasis showed its expression depends on SAP1.\",\n      \"evidence\": \"SAP1 deletion in P. yoelii with RT-PCR and protein expression analysis of UIS3\",\n      \"pmids\": [\"18466298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve whether regulation is transcriptional stability or translational\", \"Does not establish a direct SAP1-UIS3 molecular link\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining UIS3 at atomic resolution revealed a novel all-alpha-helical fold with a lipid-binding pocket occupied by phosphatidylethanolamine, giving the first structural basis for a biochemical function.\",\n      \"evidence\": \"X-ray crystallography of the PfUIS3 soluble domain at 2.5 A with liposome lipid-binding assays; PVM localization reported alongside\",\n      \"pmids\": [\"18577521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of PE binding in liver-stage development not established\", \"Structure covers only the soluble domain, not the transmembrane context\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Testing the proposed lipid-transfer model, NMR found no direct UIS3-L-FABP interaction, revising the earlier host-partner hypothesis.\",\n      \"evidence\": \"Solution NMR (1H,15N HSQC) with residue-level interaction analysis of PfUIS3 soluble domain and L-FABP\",\n      \"pmids\": [\"23169100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab negative result\", \"Does not exclude an indirect or full-length/membrane-dependent interaction\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Explaining how the parasite evades host defense, UIS3 was shown to bind host LC3 non-canonically and competitively block autophagy-mediated parasite elimination.\",\n      \"evidence\": \"Co-IP/pulldown, competition binding with LC3-interacting proteins, and uis3(-) survival assays in autophagy-proficient vs -deficient hepatocytes (P. berghei)\",\n      \"pmids\": [\"29109477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the non-canonical LC3 interface not fully resolved\", \"Does not distinguish LC3 from other Atg8 subfamily members as the operative restriction factor\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"To prove causality and test druggability of the evasion mechanism, small-molecule disruption of the UIS3-LC3 interface triggered autophagy-dependent parasite clearance.\",\n      \"evidence\": \"Docking screen, biophysical confirmation of C4-mediated disruption, and infection assays in autophagy-sufficient vs -deficient cells (P. berghei)\",\n      \"pmids\": [\"33214643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy and selectivity of C4 not established\", \"Does not address the GABARAP-dependent restriction arm\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolving which host pathway restricts UIS3-deficient parasites, genetic dissection showed restriction is GABARAP-dependent but autophagy- and LC3-independent, refining the evasion model.\",\n      \"evidence\": \"Panel of host autophagy-gene and Atg8-family knockouts with uis3(-) P. berghei growth quantification\",\n      \"pmids\": [\"33771680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of GABARAP-mediated restriction not defined\", \"Whether UIS3 itself engages GABARAPs is not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how UIS3's PE-binding activity and PVM residence mechanistically connect to its host LC3/GABARAP-directed immune evasion function, and whether these represent one integrated activity or separable roles.\",\n      \"evidence\": \"No timeline discovery links the lipid-binding pocket to the LC3-binding/autophagy-evasion function\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of UIS3 bound to LC3\", \"Role of PE binding in vivo unknown\", \"Whether UIS3 directly engages GABARAPs is untested\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005543\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0019776\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020005\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0044406\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0075044\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"host LC3 / MAP1LC3 [#8]\",\n      \"host GABARAP (restriction of uis3(-) parasites, autophagy-independent) [#10]\",\n      \"phosphatidylethanolamine (bound ligand) [#4]\",\n      \"host L-FABP (proposed by Y2H/biochemical assay [#1, #5]; direct binding not detected by NMR [#7])\"\n    ],\n    \"other_free_text\": [\n      \"Essential for early liver-stage development; uis3(-) parasites invade hepatocytes and form a parasitophorous vacuole but arrest by ~40 h post-infection and fail to establish blood-stage infection [#0, #2].\",\n      \"Expression is post-transcriptionally dependent on SAP1 in sporozoites [#6].\",\n      \"Soluble domain adopts a novel all-alpha-helical fold with a defined lipid-binding site [#4].\",\n      \"Small molecule C4 disrupts the UIS3-LC3 interface and triggers autophagy-dependent parasite elimination [#9].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1302200","name":null,"product":"protein UIS3","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1400800","name":null,"product":"protein UIS3","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1402400","name":null,"product":"protein UIS3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"UIS3","evaluation":null}