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evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39920908","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["rifin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34991452","id":"PMC_34991452","title":"STRIDE: a command-line HMM-based identifier and sub-classifier of Plasmodium falciparum RIFIN and STEVOR variant surface antigen families.","date":"2022","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/34991452","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["rifin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38910420","id":"PMC_38910420","title":"Variable Surface Antigens of Plasmodium falciparum: Protein Families with Divergent Roles.","date":"2024","source":"Protein and 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demonstrated by surface labeling and immunoprecipitation experiments, establishing rifins as clonally variant surface antigens.\",\n      \"method\": \"Surface iodination, immunoprecipitation, fluorescence microscopy with anti-RIFIN antibodies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — surface labeling and immunoprecipitation with direct antibody detection, independently corroborated by a second contemporaneous study (PMID:10562315)\",\n      \"pmids\": [\"10430943\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RIFIN proteins (previously called rosettins) are transported to the infected erythrocyte surface and are immunogenic in natural infections; human immune sera agglutinate pRBCs under conditions where RIFIN but not PfEMP1 is detected, and RIFINs resolve into multiple isoforms (pI 5.5–6.5) by 2D electrophoresis, indicating molecular microheterogeneity.\",\n      \"method\": \"Surface radioiodination, immunoprecipitation, 2D electrophoresis, flow cytometry agglutination assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods, replication across fresh isolates and in vitro lines, consistent with PMID:10430943\",\n      \"pmids\": [\"10562315\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RIFIN and PfEMP1 share a common trafficking pathway to the infected erythrocyte surface: both antigens co-traffic through single small vesicles budding from the parasitophorous vacuolar membrane, then through large multimeric vesicles (LMV) that associate with Maurer's cleft antigen Pf332, with RIFINs and PfEMP1 co-localizing at the outer rim of the LMV while Pf332 occupies the core.\",\n      \"method\": \"Immunofluorescence microscopy with co-staining of RIFIN-specific and PfEMP1-specific antibodies, fluorescent lipid (BODIPY-Ceramide) staining, live cell imaging of vesicle dynamics\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — indirect immunofluorescence with multiple antibodies in single lab, no genetic or biochemical reconstitution\",\n      \"pmids\": [\"14668007\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A specific RIFIN (PFI0050c) tagged internally with GFP is exported to Maurer's clefts (MC) in the erythrocyte cytosol, whereas C-terminal GFP tagging of the full-length protein retains it inside the parasite; removal of C-terminal sequences restores MC targeting. The variable region of the RIFIN-GFP chimera is exposed to the erythrocyte cytosol. Trafficking of both chimeras in young ring stages is sensitive to Brefeldin A, implicating the secretory pathway.\",\n      \"method\": \"Transfection with GFP-tagged RIFIN constructs (internal and C-terminal tags), live fluorescence microscopy, selective membrane permeabilization, Brefeldin A treatment\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfection with tagged constructs and multiple topology probes in single lab; functional BFA sensitivity experiment adds mechanistic depth\",\n      \"pmids\": [\"17014697\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A-type RIFINs are transported to the infected erythrocyte surface via Maurer's clefts and localize to the apical region of merozoites, whereas B-type RIFINs are mostly retained inside the parasite and localize to the merozoite cytosol. Both subtypes are expressed in merozoites, indicating antigenic variation extends to non-erythrocytic stages.\",\n      \"method\": \"Indirect immunofluorescence assay (IFA) with subtype-specific antibodies, subcellular fractionation, confocal microscopy across intraerythrocytic developmental stages and merozoites\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — IFA with multiple antibodies across stages, single lab, no functional rescue or genetic validation\",\n      \"pmids\": [\"17719658\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In a splenectomized malaria patient whose parasites lacked sequestration capacity, A-type rif genes (along with var and stevor) were not expressed, while B-type rif genes were transcribed; upon in vitro cultivation the parasites began expressing A-type RIFINs and concurrently developed the ability to adhere to endothelial receptors (CD36, ICAM-1). This supports a role for A-type RIFINs in erythrocyte sequestration and identifies B-type RIFINs as not required for sequestration.\",\n      \"method\": \"Ex vivo parasite analysis from a clinical case, quantitative RT-PCR for rif subtype expression, in vitro adhesion assays to CD36 and ICAM-1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis-like in vivo natural experiment with functional adhesion readout, but single clinical case without controlled genetic manipulation\",\n      \"pmids\": [\"19826486\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Promoter titration using episomal rif promoters downregulates not only the rif family but also var, stevor, and Pfmc-2TM families, and transcriptionally active promoters from different families colocalize within the same subnuclear expression site. This demonstrates that rif gene activation shares a common limiting titratable trans-acting factor and subnuclear compartment with other clonally variant gene families.\",\n      \"method\": \"Episomal promoter titration transfection, quantitative RT-PCR, fluorescence in situ hybridization (nuclear colocalization)\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via promoter competition, two orthogonal readouts (qRT-PCR + FISH), single lab\",\n      \"pmids\": [\"19708920\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Gametocytes express A-type and B-type RIFIN variants with distinct subcellular distributions: A-type RIFINs accumulate in discrete punctate structures at the infected erythrocyte membrane in a crescent-shaped pattern, while B-type RIFINs remain associated with the parasite. Transcription analysis reveals group-specific regulation of A-type RIFINs versus variant-specific regulation of B-type RIFINs during sexual differentiation.\",\n      \"method\": \"Immunofluorescence with subtype-specific antibodies across gametocyte stages, quantitative RT-PCR for subtype-specific transcripts, phylogenetic analysis of rif upstream regions\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — IFA plus qRT-PCR across multiple stages, single lab, no genetic functional validation\",\n      \"pmids\": [\"19020666\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Plasmepsin V (an endoplasmic reticulum protease) cleaves the N-terminal PEXEL motif of RIFIN proteins, a processing event required for their export from the parasite. A lysine at the P3 position of the PEXEL blocks Plasmepsin V activity, defining the substrate specificity governing which proteins can enter this export pathway.\",\n      \"method\": \"In vitro Plasmepsin V cleavage assays with RIFIN N-terminal peptides, site-directed mutagenesis of PEXEL residues, transfection of tagged RIFIN constructs\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis defining substrate specificity, single lab with multiple substrates\",\n      \"pmids\": [\"23387285\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Topological studies using confocal and immunoelectron microscopy and selective permeabilization reveal that the semi-conserved N-terminal region of A-type RIFINs (and some STEVORs) is exposed at the erythrocyte surface. At Maurer's clefts, the semi-conserved N-terminal and variable regions face the erythrocyte cytoplasm (cleft lumen). These data challenge the two-transmembrane topology model and suggest a single membrane-spanning topology for RIFINs.\",\n      \"method\": \"Confocal microscopy, immunoelectron microscopy, selective membrane permeabilization with streptolysin O or saponin, immunoblot of fractionated membranes\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal localization and topology methods in a single comparative study, no in vitro reconstitution\",\n      \"pmids\": [\"26173856\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A subset of RIFIN proteins binds to the inhibitory immune receptor LILRB1 and another subset binds to LAIR1, expressed on B cells and NK cells. LILRB1-binding RIFINs inhibit the activation of LILRB1-expressing B cells and NK cells in vitro. Infected erythrocytes from severe malaria patients more frequently interact with LILRB1 than those from non-severe cases.\",\n      \"method\": \"Recombinant RIFIN expression, binding assays (surface plasmon resonance, flow cytometry), reporter assays for LILRB1 signaling inhibition, B cell and NK cell activation assays, clinical isolate LILRB1-binding assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — receptor binding confirmed biochemically, signaling inhibition demonstrated in primary immune cells, replicated across multiple RIFIN variants\",\n      \"pmids\": [\"29186116\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human monoclonal antibodies that broadly recognize P. falciparum-infected erythrocytes from different isolates do so by binding to RIFIN family members. These antibodies acquired broad reactivity through insertion of the LAIR1 collagen-binding domain (98 amino acids) between V and DJ immunoglobulin segments; the LAIR1 insert is both necessary and sufficient for RIFIN binding.\",\n      \"method\": \"Isolation of human B-cell clones, sequencing of antibody genes, domain-deletion and mutagenesis of LAIR1 insert, binding assays to infected erythrocytes and recombinant RIFINs, opsonization assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic dissection with domain deletions and mutagenesis, binding confirmed biochemically, two independent donors\",\n      \"pmids\": [\"26700814\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of a RIFIN bound to LILRB1 shows that this RIFIN mimics the binding mode of the natural LILRB1 ligand MHC class I. A single point mutation in the RIFIN disrupts the complex, blocks LILRB1 binding across all tested RIFINs, and abolishes LILRB1 signaling in a reporter assay. In a supported lipid bilayer NK-cell model, RIFIN is recruited to the immunological synapse and reduces NK-cell activation (perforin mobilization).\",\n      \"method\": \"X-ray crystallography of RIFIN–LILRB1 complex, site-directed mutagenesis, LILRB1 reporter signaling assay, supported lipid bilayer NK-cell activation assay with perforin readout\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation and functional NK-cell assay, all in one study\",\n      \"pmids\": [\"32650338\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A specific RIFIN protein was identified as a ligand for the inhibitory receptor LILRB2 using a RIFIN expression library screening approach. The RIFIN binds to domain 3 of LILRB2, while LILRB2 domains 1 and 2 mediate binding to HLA class I, indicating a distinct but partially overlapping interface from LILRB1.\",\n      \"method\": \"RIFIN expression library screen, flow cytometry binding assays with LILRB2-expressing cells, domain deletion mapping of LILRB2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — library-based identification plus domain deletion mapping, single lab, no structural data\",\n      \"pmids\": [\"33647792\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal and cryo-EM structures of a RIFIN in complex with LILRB1 D3D4 or a D3D4-containing antibody Fab reveal that RIFINs bind to LILRB1 domain 3 (D3). The RIFIN-LILRB1 D3 interaction is similar in mode to the RIFIN-LAIR1 interaction. The Fab adopts an unconventional triangular architecture with inserted LILRB1 domains opening the VH-CH1 elbow.\",\n      \"method\": \"Crystal structure determination, cryo-EM structure determination, mass spectrometry identification, binding assays with LILRB1 domain constructs\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two structural methods (crystal + cryo-EM) with binding assay validation, large panel of RIFINs identified\",\n      \"pmids\": [\"33790470\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of two different RIFINs bound to LAIR1 show that both RIFINs engage similar binding sites on LAIR1 but at different angles; the RIFIN-binding sites overlap with LAIR1's collagen-binding site. The two RIFINs use completely different binding sites to engage LAIR1 versus LILRB1, indicating structural plasticity in RIFIN binding interfaces. RIFINs were confirmed to induce LAIR1-mediated cell signaling, and LAIR1-containing antibodies block this pathway.\",\n      \"method\": \"X-ray crystallography of RIFIN–LAIR1 complexes (two distinct RIFINs), LAIR1-mediated signaling assay, antibody blocking assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of two independent RIFIN–LAIR1 complexes with functional signaling and blocking assays, single lab\",\n      \"pmids\": [\"34433057\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Negative-stain EM defines the architecture of LAIR1-inserted antibodies against RIFINs; crystal structures of RIFIN-V2 domain bound to LAIR1 reveal a hydrophobic, membrane-distal LAIR1-binding region on RIFIN with extensive structural diversity across variants, engaging LAIR1 in a 1:1 fashion. A structure-derived LAIR1-binding sequence signature identified >20 LAIR1-binding RIFINs, including some from field strains and from Plasmodium species infecting gorillas and chimpanzees.\",\n      \"method\": \"Negative-stain EM, X-ray crystallography of RIFIN–LAIR1 complexes, structural and sequence analysis, binding assays with LAIR1 constructs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with EM validation and sequence analysis, single lab with diverse RIFIN panel\",\n      \"pmids\": [\"34244481\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The C-terminus of a P. falciparum rifin prevents GFP export when fused to a KAHRP-like export-competent N-terminus in P. berghei, demonstrating that the RIFIN C-terminal domain contains a retention/sorting signal that actively prevents surface export.\",\n      \"method\": \"Transfection of GFP fusion constructs with RIFIN C-terminal sequences in P. berghei, fluorescence microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — heterologous export assay in P. berghei with defined domain swaps, single lab, single construct series\",\n      \"pmids\": [\"20419102\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Insertion experiments in a cell-free ER membrane system demonstrate that for RIFIN proteins, transmembrane segments TM1 and TM3 integrate into the ER membrane establishing an Ncyt-Ccyt topology, while the segment predicted to be TM2 is translocated to the ER lumen rather than spanning the membrane, challenging the classical two-transmembrane model.\",\n      \"method\": \"In vitro ER membrane insertion assay using N-linked glycosylation as topology reporter, cell-free translation system\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of membrane insertion with defined topology readout, single lab, three RIFIN proteins tested\",\n      \"pmids\": [\"31821735\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Export of RIFIN (a PEXEL-positive protein) from the ER is decreased by expression of dominant-negative (inactive) mutants of either PfRab1b or PfArf1 GTPases, suggesting that RIFIN export from the ER is sequentially regulated by both PfArf1 and PfRab1b, while a PEXEL-negative protein (PfAK2) uses only PfArf1.\",\n      \"method\": \"Co-immunoprecipitation of PfRab5b-associated proteins, expression of active/inactive GTPase mutants, indirect immunofluorescence, fluorescence quantification of RIFIN export\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dominant-negative approach with functional export readout, two GTPases tested, single lab\",\n      \"pmids\": [\"33604307\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional deletion of the chromodomain of a chromodomain-containing protein (PfCDP) that binds H3K9me3 causes selective upregulation of a subset of rifin genes (along with some var and stevor genes), and PfCDP knockout parasites show increased RBC rosette formation, establishing PfCDP/H3K9me3 as an epigenetic repressor of a subset of RIFIN expression and a regulator of rosetting.\",\n      \"method\": \"Inducible DiCre-LoxP conditional knockout, qRT-PCR for rif transcripts, immunofluorescence for RIFIN protein, rosetting assays, chromatin immunoprecipitation for H3K9me3 binding\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic knockout with defined functional rosetting readout and ChIP evidence, single lab\",\n      \"pmids\": [\"35460670\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional knockdown of PfBDP7 or PfBDP1 (bromodomain proteins) results in de-repression of variant surface antigen genes including rifins at both mRNA and protein levels. ChIP-seq shows PfBDP7 and PfBDP1 are enriched in heterochromatic regions across the gene body of rifin (and other VSA) genes in early schizonts, establishing these bromodomain proteins as components of RIFIN gene silencing through heterochromatin association.\",\n      \"method\": \"Conditional knockdown, RT-PCR and immunofluorescence for RIFIN expression, ChIP-seq for PfBDP7 and PfBDP1 genome-wide binding\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic knockdown with genome-wide ChIP-seq mapping, single lab, two proteins validated\",\n      \"pmids\": [\"35493110\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human antibodies to RIFIN (alongside antibodies to PfEMP1) are sufficient to promote NK-cell-dependent antibody-dependent cellular cytotoxicity (ADCC) and inhibit P. falciparum parasite growth in vitro, establishing RIFINs as functional targets of NK-mediated ADCC.\",\n      \"method\": \"IgG isolation from malaria-immune adults, ADCC assay with primary human NK cells, parasite growth inhibition assay, infected RBC lysis measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ADCC assay with primary NK cells and growth inhibition readout, anti-RIFIN IgG identified as sufficient, single lab\",\n      \"pmids\": [\"29943728\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A clade of RIFINs binds to the inhibitory NK-cell receptor KIR2DL1 more strongly than the natural human ligand MHC class I, mediates inhibitory signaling, and suppresses KIR2DL1-expressing NK-cell activation. The same KIR2DL1-binding RIFINs also bind to the cognate activating receptor KIR2DS1, resulting in activation of KIR2DS1-expressing NK cells, identifying RIFINs as the first pathogen-derived ligands for a human activating killer immunoglobulin-like receptor.\",\n      \"method\": \"RIFIN expression library screening, binding assays (flow cytometry, surface plasmon resonance), NK-cell activation assays with KIR2DL1- and KIR2DS1-expressing NK cells, structural analysis of RIFIN–KIR2DL1 interaction, analysis of field-isolated strains\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical binding assays, primary NK-cell functional assays, structural characterization, validated across field strains from two continents\",\n      \"pmids\": [\"40500441\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A subset of RIFINs engages LILRB1 through a conserved structural motif anchored by disulfide-bonded cysteines, despite extensive sequence diversity across the RIFIN family. LILRB1 binds these RIFINs and MHC-I through overlapping interfaces, confirmed by crystallographic analysis and surface plasmon resonance.\",\n      \"method\": \"Protein microarray immunoprofiling, logistic regression to identify RIFIN–severity associations, surface plasmon resonance binding assays, X-ray crystallography of LILRB1–RIFIN complexes, synthetic peptide interaction studies\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of LILRB1–RIFIN complexes with SPR binding validation and structural motif identification, single lab with multiple RIFINs\",\n      \"pmids\": [\"41314148\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"RIFIN proteins (encoded by the large rif multigene family) are exported via Plasmepsin V-mediated PEXEL cleavage and ER-to-surface trafficking regulated by PfArf1 and PfRab1b GTPases, trafficked through Maurer's clefts to the infected erythrocyte surface with a single-spanning transmembrane topology (Ncyt-Ccyt); at the surface, a subset of A-type RIFINs engage host inhibitory immune receptors LILRB1, LILRB2, LAIR1, and KIR2DL1 by mimicking the binding mode of their natural ligands (MHC class I and collagen), thereby suppressing B-cell, NK-cell, and adaptive immune responses, while another clade binds the activating receptor KIR2DS1 to recruit NK cell killing; RIFIN gene expression is epigenetically silenced by PfBDP1/PfBDP7 bromodomain proteins and a chromodomain protein (PfCDP) that reads H3K9me3, and B-type RIFINs are not required for erythrocyte sequestration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RIFIN proteins, encoded by the large rif multigene family, are clonally variant antigens displayed on the surface of P. falciparum-infected erythrocytes and are immunogenic in natural infection [#0, #1]. They reach the surface through the parasite's protein-export pathway: the endoplasmic reticulum protease Plasmepsin V cleaves the RIFIN N-terminal PEXEL motif — a processing step gated by the P3 residue and required for export [#8] — after which ER exit depends sequentially on the PfArf1 and PfRab1b GTPases [#19], with trafficking proceeding through Maurer's clefts to the erythrocyte membrane [#3, #9]. RIFINs adopt a single membrane-spanning Ncyt-Ccyt topology in which TM2 is translocated into the ER lumen rather than crossing the membrane, and the semi-conserved N-terminal region is exposed at the erythrocyte surface, revising the earlier two-transmembrane model [#18, #9]; a C-terminal sorting signal actively restrains export [#3, #17]. A functional dichotomy separates surface-exported A-type RIFINs, which correlate with cytoadherence to CD36 and ICAM-1, from mostly parasite-retained B-type RIFINs that are dispensable for sequestration [#4, #5]. At the erythrocyte surface, a major role of RIFINs is subversion of host immunity: distinct RIFIN subsets bind the inhibitory receptors LILRB1, LILRB2, and LAIR1 and dampen B-cell and NK-cell activation, with severe-malaria isolates preferentially engaging LILRB1 [#10, #13]. Structural studies show RIFINs mimic the binding modes of the natural receptor ligands — engaging LILRB1 domain 3 analogously to MHC class I and overlapping the collagen-binding site of LAIR1 — while using structurally plastic, disulfide-anchored interfaces conserved despite sequence diversity [#12, #14, #15, #16, #24]. A distinct RIFIN clade binds the inhibitory receptor KIR2DL1 to suppress NK cells and simultaneously binds its activating counterpart KIR2DS1 to trigger NK activation [#23]. RIFINs are also targets of protective humoral immunity: broadly reactive human antibodies acquire RIFIN specificity by inserting the LAIR1 collagen-binding domain into their variable region, and anti-RIFIN IgG drives NK-mediated antibody-dependent cellular cytotoxicity against infected cells [#11, #22]. Expression of the family is epigenetically silenced through heterochromatin, with the H3K9me3-reading chromodomain protein PfCDP and the bromodomain proteins PfBDP1/PfBDP7 repressing subsets of rif genes and, in the case of PfCDP loss, promoting rosette formation [#20, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that RIFINs are displayed on the infected-erythrocyte surface defined them as a novel class of clonally variant surface antigens accessible to the host immune system.\",\n      \"evidence\": \"Surface iodination, immunoprecipitation, and antibody-based fluorescence/agglutination across isolates\",\n      \"pmids\": [\"10430943\", \"10562315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve subtype-specific behavior of individual RIFIN variants\", \"No functional role beyond surface exposure assigned\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tracing RIFIN trafficking showed it co-routes with PfEMP1 through vesicular intermediates and Maurer's clefts, placing RIFIN within the shared surface-antigen export machinery.\",\n      \"evidence\": \"Immunofluorescence co-staining, lipid vesicle imaging, and live-cell vesicle dynamics\",\n      \"pmids\": [\"14668007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect IFA without genetic or biochemical reconstitution\", \"Molecular components of the vesicle route not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tagging experiments localized the export/retention determinants to specific RIFIN regions, showing the C-terminus blocks surface targeting and the variable region faces the erythrocyte cytosol at Maurer's clefts.\",\n      \"evidence\": \"GFP-tagged RIFIN constructs, selective permeabilization, and Brefeldin A sensitivity in P. falciparum 3D7\",\n      \"pmids\": [\"17014697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GFP tagging may perturb native trafficking\", \"Trans-acting factors reading the C-terminal signal not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A heterologous export assay confirmed the RIFIN C-terminal domain carries an active retention/sorting signal that overrides an export-competent N-terminus.\",\n      \"evidence\": \"GFP fusion domain swaps expressed in P. berghei with fluorescence readout\",\n      \"pmids\": [\"20419102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shown in a heterologous rodent-malaria system, not P. falciparum\", \"Signal recognition machinery unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying Plasmepsin V as the protease that cleaves the RIFIN PEXEL motif defined the entry point into the export pathway and the sequence rules that gate it.\",\n      \"evidence\": \"In vitro Plasmepsin V cleavage of RIFIN peptides with PEXEL mutagenesis\",\n      \"pmids\": [\"23387285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream trafficking steps after cleavage not addressed\", \"In vitro assay may not capture all in vivo determinants\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Broadly reactive human antibodies were shown to recognize RIFINs via an inserted LAIR1 collagen-binding domain, revealing both a shared RIFIN epitope and an unusual antibody diversification mechanism.\",\n      \"evidence\": \"Human B-cell cloning, antibody gene sequencing, LAIR1-insert deletion/mutagenesis, and binding assays\",\n      \"pmids\": [\"26700814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native RIFIN ligand implied by LAIR1 insert not yet defined\", \"Protective significance in vivo unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Topology mapping placed the semi-conserved N-terminus at the cell surface and challenged the two-transmembrane model, redefining how RIFINs are oriented in the erythrocyte membrane.\",\n      \"evidence\": \"Confocal and immunoelectron microscopy with selective permeabilization and membrane fractionation\",\n      \"pmids\": [\"26173856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topology inferred from antibody accessibility, not reconstitution\", \"Physiological consequences of single-span topology unaddressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that RIFIN subsets bind the inhibitory receptors LILRB1 and LAIR1 and suppress immune-cell activation established immune evasion as a core RIFIN function linked to disease severity.\",\n      \"evidence\": \"Recombinant RIFIN binding (SPR, flow cytometry), signaling and B/NK activation assays, and clinical isolate LILRB1-binding correlation\",\n      \"pmids\": [\"29186116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of receptor engagement not yet defined\", \"Which native RIFIN variants dominate in vivo unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cell-free ER insertion assays resolved the topology debate by showing TM1 and TM3 integrate while the predicted TM2 is translocated to the lumen, confirming a single-spanning Ncyt-Ccyt architecture.\",\n      \"evidence\": \"In vitro ER membrane insertion with N-glycosylation topology reporters in cell-free translation\",\n      \"pmids\": [\"31821735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tested three RIFINs; family-wide generality assumed\", \"In vitro system may not reflect final erythrocyte-membrane topology\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Dominant-negative GTPase experiments defined PfArf1 and PfRab1b as sequential regulators of RIFIN ER exit, distinguishing PEXEL-positive from PEXEL-negative export routes.\",\n      \"evidence\": \"Active/inactive PfRab1b and PfArf1 mutants with immunofluorescence export quantification\",\n      \"pmids\": [\"33604307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GTPase-RIFIN interaction not demonstrated\", \"Order of action inferred rather than directly resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The RIFIN-LILRB1 crystal structure showed RIFINs mimic the MHC-I binding mode, and a single mutation abolishing binding and signaling proved this interaction drives NK-cell suppression.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis, LILRB1 reporter signaling, and supported-bilayer NK-cell perforin assay\",\n      \"pmids\": [\"32650338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single RIFIN-LILRB1 pair crystallized\", \"In vivo contribution to immune escape not quantified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural and mapping studies extended RIFIN immune targeting to LILRB2 domain 3 and defined the LILRB1 D3 and LAIR1 collagen-site interfaces, revealing structurally plastic RIFIN-binding surfaces conserved across diverse variants.\",\n      \"evidence\": \"Crystal/cryo-EM structures, expression-library screens, and domain-mapping binding assays for LILRB2, LILRB1, and LAIR1\",\n      \"pmids\": [\"33647792\", \"33790470\", \"34433057\", \"34244481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each receptor in natural infection unclear\", \"How a single RIFIN chooses between distinct receptor interfaces not fully explained\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic and ChIP studies established that the H3K9me3-reader PfCDP and the bromodomain proteins PfBDP1/PfBDP7 silence subsets of rif genes through heterochromatin, linking RIFIN epigenetic control to rosetting.\",\n      \"evidence\": \"Conditional knockout/knockdown, qRT-PCR and IFA for RIFIN, ChIP/ChIP-seq for H3K9me3 and BDP binding, and rosetting assays\",\n      \"pmids\": [\"35460670\", \"35493110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only subsets of rif genes affected; variant selectivity mechanism unresolved\", \"Direct causal link between specific RIFIN derepression and rosetting not isolated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a RIFIN clade binding both inhibitory KIR2DL1 and activating KIR2DS1 revealed RIFINs as the first pathogen ligands for an activating KIR, expanding the receptor repertoire of RIFIN-mediated NK modulation, while a conserved disulfide-anchored motif was defined for LILRB1 engagement.\",\n      \"evidence\": \"Expression-library screens, SPR/flow binding, KIR2DL1/KIR2DS1 NK-activation assays, crystallography, and field-strain analysis\",\n      \"pmids\": [\"40500441\", \"41314148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Net in vivo balance of inhibitory versus activating NK outcomes unresolved\", \"Host KIR-genotype dependence of these interactions not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how specific RIFIN variants are selected for surface display versus retention, and how the balance of inhibitory versus activating host-receptor engagement is coordinated during natural infection to determine disease outcome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanism linking variant expression choice to specific receptor engagement\", \"In vivo consequences of simultaneous inhibitory and activating NK signaling unquantified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005102\", \"supporting_discovery_ids\": [10, 12, 13, 14, 15, 16, 23, 24]},\n      {\"term_id\": \"GO:0042605\", \"supporting_discovery_ids\": [11, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020030\", \"supporting_discovery_ids\": [0, 1, 4, 9]},\n      {\"term_id\": \"GO:0020036\", \"supporting_discovery_ids\": [2, 3, 4, 9]},\n      {\"term_id\": \"GO:0005789\", \"supporting_discovery_ids\": [8, 18, 19]},\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [18, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0046796\", \"supporting_discovery_ids\": [2, 3, 8, 19]},\n      {\"term_id\": \"GO:0052572\", \"supporting_discovery_ids\": [10, 12, 15, 23]},\n      {\"term_id\": \"GO:0007155\", \"supporting_discovery_ids\": [5, 20]},\n      {\"term_id\": \"GO:0006325\", \"supporting_discovery_ids\": [6, 20, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Plasmepsin V (PEXEL cleavage) [#8]\",\n      \"PfArf1 GTPase (ER export) [#19]\",\n      \"PfRab1b GTPase (ER export) [#19]\",\n      \"Human LILRB1 [#10, #12, #14, #24]\",\n      \"Human LILRB2 (domain 3) [#13]\",\n      \"Human LAIR1 [#10, #15, #16]\",\n      \"Human KIR2DL1 (inhibitory) [#23]\",\n      \"Human KIR2DS1 (activating) [#23]\",\n      \"PfCDP chromodomain protein (H3K9me3 reader, repressor) [#20]\",\n      \"PfBDP1 bromodomain protein (repressor) [#21]\",\n      \"PfBDP7 bromodomain protein (repressor) [#21]\"\n    ],\n    \"other_free_text\": [\n      \"Clonally variant surface antigen of P. falciparum-infected erythrocytes, immunogenic in natural infection [#0, #1].\",\n      \"A-type RIFINs are surface-exported and associated with cytoadherence to CD36/ICAM-1; B-type RIFINs are mostly parasite-retained and dispensable for sequestration [#4, #5].\",\n      \"Single membrane-spanning Ncyt-Ccyt topology with luminal TM2, revising the two-transmembrane model [#18, #9]; C-terminal domain carries a retention/sorting signal [#3, #17].\",\n      \"RIFINs mimic natural MHC-I and collagen ligand binding modes and use structurally plastic, disulfide-anchored interfaces conserved across diverse variants [#12, #15, #24].\",\n      \"Anti-RIFIN antibodies drive NK-mediated antibody-dependent cellular cytotoxicity and can acquire specificity via LAIR1 collagen-domain insertion [#22, #11].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0100600","name":null,"product":"rifin","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}