{"gene":"TRIM5","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2004,"finding":"TRIM5α (a component of cytoplasmic bodies) restricts HIV-1 infection in Old World monkey cells at a post-entry, pre-reverse transcription step; the block is species-specific, acts on the incoming viral capsid, and is relieved by TRIM5α knockdown.","method":"siRNA knockdown, retroviral infectivity assays, subcellular localization by immunofluorescence","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function (siRNA) with defined cellular phenotype, replicated across multiple labs in the same year","pmids":["14985764"],"is_preprint":false},{"year":2004,"finding":"TRIM5α restricts both HIV-1 and N-tropic murine leukemia virus (N-MLV), indicating broader antiretroviral specificity determined by the viral capsid; human, rhesus, and African green monkey TRIM5α variants show different but overlapping restriction spectra.","method":"Overexpression of TRIM5α orthologs in permissive cells, retroviral infectivity assays with capsid mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthologs tested with panel of capsid mutants, replicated independently","pmids":["15249690","15249685","15249687"],"is_preprint":false},{"year":2004,"finding":"In owl monkeys, a LINE-1 retrotransposon-mediated insertion of a CypA cDNA into the TRIM5 locus creates a TRIM5-CypA fusion protein (TRIMCyp) that restricts HIV-1 through CypA-dependent capsid recognition; this fusion accounts for post-entry HIV-1 restriction in owl monkey cells.","method":"RNAi knockdown, cDNA cloning, transfer of TRIMCyp to human/rat cells, cyclosporin A inhibition assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi, functional transfer, pharmacological inhibition; independently confirmed by multiple labs","pmids":["15243629","15326303"],"is_preprint":false},{"year":2006,"finding":"TRIM5α orthologs from Old World monkeys specifically associate with the HIV-1 capsid via the B30.2 domain; this interaction promotes rapid, premature capsid disassembly (accelerated uncoating) as shown by loss of particulate capsid and gain of soluble capsid protein. Proteasome inhibition does not abrogate restriction.","method":"Capsid binding assays, quantification of particulate vs. soluble capsid after infection, proteasome inhibitor treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct capsid binding assay plus biochemical uncoating readout, replicated in multiple TRIM5 variants","pmids":["16540544"],"is_preprint":false},{"year":2006,"finding":"Human TRIM5α mediates accelerated uncoating (premature conversion of particulate to soluble capsid) of N-MLV in a capsid residue 110-dependent manner; domains required for potent restriction are also required for capsid disassembly.","method":"Quantification of particulate vs. soluble MLV capsid in infected cells, domain deletion mutants, capsid residue 110 mutants","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical capsid disassembly assay with domain mutants and viral capsid mutants, single lab","pmids":["17135314"],"is_preprint":false},{"year":2006,"finding":"TRIM5α is rapidly turned over (half-life ~50–60 min) via polyubiquitylation dependent on intact RING and B-box 2 domains; proteasome inhibition triggers aggresome formation containing TRIM5α, polyubiquitylated proteins, heat shock proteins, and dynein.","method":"Pulse-chase half-life assays, domain mutant analysis, proteasome inhibitor treatment, immunofluorescence co-localization","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pulse-chase, domain mutants, pharmacological inhibition with multiple orthogonal readouts, single lab","pmids":["16472833"],"is_preprint":false},{"year":2006,"finding":"Proteasome inhibition of TRIM5α-restricted cells allows reverse transcription products to accumulate even though infection remains blocked, indicating TRIM5α restricts retroviral infection at multiple steps; pre-integration complexes generated under proteasome inhibition are competent for integration in vitro.","method":"Proteasome inhibitor treatment, quantitative PCR for reverse transcription products, in vitro integration assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple TRIM5 variants tested, in vitro integration assay, replicated across multiple restriction factors","pmids":["16973579"],"is_preprint":false},{"year":2005,"finding":"TRIM5α oligomerizes into trimers; the coiled-coil and B30.2(SPRY) domains contribute to trimer formation/stability. A RING/B-box 2-deleted dominant-negative TRIM5α forms heterotrimers with wild-type TRIM5α, explaining the dominant-negative effect.","method":"Analytical ultracentrifugation, co-immunoprecipitation, gel filtration, dominant-negative assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biophysical methods but later work shows dimers are the predominant species; single lab","pmids":["16254380"],"is_preprint":false},{"year":2008,"finding":"Recombinant TRIM5α (TRIM5-21R chimera) is predominantly dimeric; it has E3 ubiquitin ligase activity (auto-ubiquitylation with multiple E2 enzymes in vitro) and directly binds HIV-1 CA-NC assemblies via the SPRY domain V1 loop without other mammalian proteins.","method":"Analytical ultracentrifugation, in vitro ubiquitylation assay, direct capsid binding assay with purified recombinant protein","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of E3 ligase activity and direct capsid binding with pure recombinant protein, multiple orthogonal methods, single lab","pmids":["18799573"],"is_preprint":false},{"year":2008,"finding":"TRIM5α functions as a RING-finger E3 ubiquitin ligase in vitro and in vivo, auto-ubiquitinates in cooperation with UbcH5B, is also ubiquitinated by Ro52 (another E3 ligase), and deubiquitinated by Yersinia effector YopJ. Monoubiquitination of TRIM5α signals its translocation from cytoplasmic bodies to the cytoplasm.","method":"In vitro ubiquitylation assay, overexpression/co-IP, monoubiquitin-fusion assay, confocal microscopy","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro E3 assay plus cellular localization assay, single lab, multiple orthogonal methods","pmids":["18312418"],"is_preprint":false},{"year":2008,"finding":"Encounter with a restriction-sensitive retroviral core causes rapid proteasome-dependent degradation of TRIM5α; this occurs specifically with restrictive TRIM5α-capsid pairs (rhesus TRIM5α with HIV-1, human TRIM5α with N-MLV, TRIMCyp with HIV-1) and is prevented by proteasome inhibitors or CsA.","method":"Western blot of TRIM5α levels after virus inoculation, proteasome inhibitor treatment, CsA treatment, endogenous TRIM5α measurement in rhesus cells","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple restriction factor/virus pairs tested, endogenous protein measured, pharmacological controls, single lab with strong internal replication","pmids":["18497858"],"is_preprint":false},{"year":2009,"finding":"The TRIM5α B-box 2 domain has an unusual hydrophobic surface patch (cluster 1) and flanking Arg121 that are required for higher-order self-association and avid capsid binding, which are the major mechanisms by which B-box 2 potentiates HIV-1 restriction (not turnover or cytoplasmic body formation).","method":"NMR structure of B-box 2 domain, site-directed mutagenesis, capsid binding assays, higher-order oligomerization assays, retroviral infectivity assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure combined with mutagenesis and functional assays, multiple orthogonal approaches, single lab","pmids":["19656869"],"is_preprint":false},{"year":2010,"finding":"Recombinant TRIM5α spontaneously assembles into two-dimensional paracrystalline hexagonal lattices; assembly requires protein dimerization and B-box 2 Arg121 but not the SPRY domain. Assembly is promoted by binding to hexagonal CA arrays, suggesting a deformable hexagonal scaffold model for retroviral capsid recognition.","method":"Electron microscopy of 2D crystalline arrays, mutagenesis, capsid array-templated assembly assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural EM of recombinant protein assemblies with mutagenesis validation, single lab","pmids":["21187419"],"is_preprint":false},{"year":2011,"finding":"TRIM5 is a RING domain E3 ubiquitin ligase that, acting with UBC13-UEV1A, catalyses synthesis of unattached K63-linked ubiquitin chains to activate TAK1 kinase and stimulate AP-1 and NF-κB innate immune signalling; interaction with the retroviral capsid lattice greatly enhances UBC13-UEV1A-dependent E3 activity; TAK1 and UBC13 contribute to capsid-specific restriction.","method":"In vitro ubiquitin chain synthesis assay, TAK1/UBC13 knockdown, NF-κB/AP-1 reporter assays, virus challenge experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of K63-ubiquitin chain synthesis, multiple loss-of-function approaches, reporter assays, mechanistic epistasis; replicated in subsequent studies","pmids":["21512573"],"is_preprint":false},{"year":2011,"finding":"Rhesus TRIM5α disrupts the HIV-1 capsid specifically at inter-hexamer interfaces; CC-SPRY domain binds CA assemblies in a concentration-dependent manner and releases protofilament fragments of CA hexamers without dissociating into monomers. Intra-hexamer crosslinking does not prevent disruption, but inter-hexamer crosslinking does.","method":"CryoEM of CA assemblies incubated with purified TRIM5α fragments, chemical crosslinking with disulfide bond-forming CA mutants","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryoEM structural analysis combined with mutagenesis and crosslinking, single lab, multiple orthogonal methods","pmids":["21455494"],"is_preprint":false},{"year":2011,"finding":"The RING domain of TRIM5α has E3 ubiquitin ligase activity; RING domain residues in the E2-binding region are required for both self-ubiquitylation and potent HIV-1 restriction, demonstrating that E3 ligase activity contributes to restriction. The NMR structure of the TRIM5α RING domain was determined.","method":"NMR structure determination, site-directed mutagenesis of RING domain, in vitro self-ubiquitylation assay, retroviral infectivity assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure, systematic mutagenesis, in vitro E3 assay linked to functional restriction, single lab","pmids":["21734049"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the rhesus TRIM5α PRY/SPRY domain reveals that capsid binding is mediated by flexible hypervariable loops (including the mobile v1 segment) that map to the structurally divergent face, paralleling antigen recognition by IgM antibodies; the monomeric PRY/SPRY alone can bind HIV-1 CA assemblies.","method":"X-ray crystallography of PRY/SPRY domain, biochemical capsid binding assay, cryoEM","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent crystal structures (two papers) with biochemical binding validation","pmids":["22847415","23091002"],"is_preprint":false},{"year":2005,"finding":"CypA is required for HIV-1 restriction by Old World monkey TRIM5α: CypA knockdown increases HIV-1 infectivity to the same extent as TRIM5 knockdown; CsA and CA mutations that disrupt CypA binding rescue HIV-1 from restriction; simultaneous CypA and TRIM5 knockdown causes no additional increase in titer, placing CypA upstream of TRIM5α.","method":"RNAi knockdown of CypA and TRIM5 (separately and combined), CsA treatment, CA mutant viruses, epistasis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via dual RNAi knockdown, pharmacological inhibition, viral capsid mutants; replicated by multiple labs","pmids":["16203999"],"is_preprint":false},{"year":2005,"finding":"TRIM5α orthologs form heteromultimers via their conserved coiled-coil domains; non-human primate TRIM5α expressed in human cells can disrupt the anti-N-MLV activity of endogenous human TRIM5α through heteromultimerization, not through the C-terminal capsid-recognition domain.","method":"Co-immunoprecipitation, dominant-negative assays, co-localization, domain deletion analysis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional dominant-negative assay with domain deletions, single lab","pmids":["15919943"],"is_preprint":false},{"year":2007,"finding":"TRIM5α cytoplasmic bodies are highly dynamic structures: they move along microtubules (saltatory and long-distance), undergo morphological changes, and TRIM5α protein rapidly exchanges between cytoplasmic bodies and diffuse cytoplasmic pools. Association with cytoplasmic bodies is not required for antiretroviral activity.","method":"Live-cell fluorescence microscopy, FRAP, photoactivation, microtubule perturbation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live imaging, FRAP, and photoactivation with functional correlation; single lab, multiple orthogonal live-cell methods","pmids":["17392513"],"is_preprint":false},{"year":2005,"finding":"Cytoplasmic body association is not required for TRIM5α antiretroviral activity: spider monkey TRIM5α restricts retroviruses without forming cytoplasmic bodies; geldanamycin (Hsp90 inhibitor) dissolves cytoplasmic bodies without affecting restriction.","method":"Overexpression of TRIM5α orthologs (GFP fusion), geldanamycin treatment, retroviral infectivity assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological disruption plus natural variant lacking bodies, single lab","pmids":["16183097"],"is_preprint":false},{"year":2005,"finding":"TRIM5α transcription is upregulated by interferons (IFN-α and IFN-β) through an ISRE element in the TRIM5α promoter; STAT1 binds to the ISRE sequence; IFN-β induces TRIM5α protein expression.","method":"Northern blot, qRT-PCR, luciferase reporter assay, EMSA, Western blot with specific antibody","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple transcriptional assays with EMSA and mutational analysis of ISRE, single lab","pmids":["16289103"],"is_preprint":false},{"year":2008,"finding":"A second, independently generated TRIM5-CypA fusion (TRIMCyp) exists in pigtailed macaques; its distinct HIV-1 restriction specificity is explained by a point mutation near the CypA:capsid-binding interface acquired during/after transposition.","method":"Genomic sequencing, functional infectivity assays, CsA inhibition, site-directed mutagenesis of CypA interface","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — convergent evolutionary example confirmed functionally with mutagenesis, independently reported by two groups","pmids":["18287034","18389077"],"is_preprint":false},{"year":2010,"finding":"When MLV infection is restricted by human TRIM5α, integrase protein and reverse transcription products are lost from cells while capsid and viral RNA are solubilized; proteasome inhibition blocks these biochemical consequences but not antiviral potency, indicating proteasomes are required for TRIM5α-induced core disruption but not restriction per se.","method":"Sucrose gradient fractionation of retroviral core components after synchronized infection, proteasome inhibitor treatment, quantitative detection of CA, integrase, viral RNA, and RT products","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — novel biochemical fractionation assay tracking multiple core components, pharmacological dissection of restriction steps, single lab","pmids":["23505372"],"is_preprint":false},{"year":2015,"finding":"TRIM5α employs E2 enzyme Ube2W to anchor K63-linked polyubiquitin chains via TRIM5α auto-ubiquitination; Ube2W monoubiquitinates TRIM5α at internal lysines (especially K45 and K50), which serves as a substrate for chain elongation by Ube2N/Ube2V2; depletion of these E2 enzymes or ubiquitin mutation inhibits restriction-associated reverse transcription block.","method":"In vitro ubiquitination reconstitution, E2 depletion by siRNA, Ub mutant analysis, MS identification of modified lysines","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus cellular loss-of-function with MS identification of modification sites, single lab","pmids":["26101372"],"is_preprint":false},{"year":2015,"finding":"RING dimerization of TRIM5α is required for activation of Ubc13 (K63-linkage-specific E2) to synthesize K63-linked polyubiquitin chains; higher-order oligomerization (promoted by capsid interaction) enhances RING dimerization and therefore E3 ligase activity.","method":"Crystal structure of TRIM5α RING:Ubc13-Ub complex, analytical ultracentrifugation, mutagenesis, in vitro ubiquitination assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical reconstitution and mutagenesis validation, single lab","pmids":["26212332"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the TRIM5α B-box 2 domain shows it can form both dimers and trimers; trimers link multiple TRIM5α proteins into a hexagonal net matching capsid lattice spacing. B-box-mediated interactions also sterically restrict RING domain dimerization, modulating E3 ligase activity.","method":"X-ray crystallography, functional mutagenesis, capsid binding and restriction assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mutagenesis and mechanistic linkage to E3 activity, single lab","pmids":["27253059"],"is_preprint":false},{"year":2016,"finding":"Human TRIM5α restricts HIV-1 in Langerhans cells (LCs) but not in subepithelial DC-SIGN+ DCs; restriction depends on HIV-1 binding to Langerin (C-type lectin), which routes HIV-1 into a TRIM5α-mediated autophagy-activating pathway; DC-SIGN binding causes TRIM5α to dissociate and abrogates restriction.","method":"siRNA knockdown of TRIM5α in primary DCs, co-IP of TRIM5α with Langerin/DC-SIGN, autophagy inhibitor assays, confocal microscopy, retroviral infectivity assays in primary cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, co-IP, pharmacological inhibition) in primary human cells, single lab","pmids":["27919079"],"is_preprint":false},{"year":2018,"finding":"Hexagonal assembly of TRIM5 on retroviral capsids triggers N-terminal polyubiquitination; trivalent RING arrangement enables elongation of N-terminally anchored K63-linked ubiquitin chains (N-K63-Ub). N-K63-Ub drives innate immune stimulation and proteasomal degradation of TRIM5; premature ubiquitination before lattice assembly triggers degradation and ablates restriction.","method":"Ubiquitin chain analysis by MS, Ub mutant TRIM5α constructs, inducible ubiquitination system, innate immune reporter assays, retroviral infectivity assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-based ubiquitin chain mapping, mechanistic dissection with multiple Ub mutants and inducible systems, single lab","pmids":["30503508"],"is_preprint":false},{"year":2019,"finding":"CypA shields HIV-1 from restriction by human TRIM5α in primary human blood cells; disruption of the CA-CypA interaction renders HIV-1 susceptible to potent human TRIM5α restriction before reverse transcription; endogenous TRIM5α associates with virion cores entering the cytoplasm only when the CA-CypA interaction is disrupted.","method":"CRISPR/CAS9 knockout and siRNA knockdown of TRIM5α in primary cells, CA-CypA mutant viruses, CsA treatment, co-fractionation of TRIM5α with incoming cores","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — primary cell gene editing, biochemical fractionation, CA mutants, pharmacological controls; definitively resolves longstanding question","pmids":["31636416"],"is_preprint":false},{"year":2019,"finding":"Immunoproteasome activation (by IFN-α) reprograms human TRIM5α for effective capsid-dependent HIV-1 restriction; the immunoproteasome accelerates TRIM5α turnover, and this is required for the switch to potent anti-HIV-1 activity; restriction is dependent on viral capsid.","method":"siRNA library screen in IFN-α-treated cells, siRNA/CRISPR knockdown of immunoproteasome subunits, HIV-1 infectivity assays, TRIM5α stability measurements","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — unbiased screen followed by mechanistic validation with multiple loss-of-function approaches, single lab","pmids":["30886358"],"is_preprint":false},{"year":2014,"finding":"TRIM5α acts as a selective autophagy receptor for HIV-1; it recognizes and targets HIV-1 for autophagic destruction and nucleates the core autophagy machinery by assembling ULK1 and BECN1 into an active complex; TRIM5α interactions with mammalian Atg8 proteins are required for this anti-HIV effector function.","method":"Co-IP of TRIM5α with autophagy components, knockdown of autophagic mediators, retroviral infectivity assays, protein interaction mapping","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and knockdown data, but subsequent study (PMID 26764007) found autophagy not required for restriction; conflicting results lower confidence","pmids":["25587751"],"is_preprint":false},{"year":2016,"finding":"Autophagic degradation of TRIM5α occurs basally (LC3b and LAMP2A co-localize with TRIM5α bodies); however, depletion of ATG5, Beclin1, or p62 by siRNA or CRISPR does not abrogate retroviral restriction by human TRIM5α, rhesus TRIM5α, or TRIMCyp, indicating autophagy is not required for restriction.","method":"siRNA and CRISPR-Cas9 depletion of autophagy mediators, retroviral infectivity assays, immunofluorescence co-localization, lysosomal inhibitor treatment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR and siRNA with multiple autophagy targets, multiple TRIM5 orthologs tested; NEGATIVE finding for autophagy requirement is well-supported","pmids":["26764007"],"is_preprint":false},{"year":2010,"finding":"Human TRIM5α affects TAB2 protein levels, abrogating TAB2-dependent NF-κB activation; human and rhesus TRIM5α also activate NF-κB reporter expression in a dose-dependent manner; distinct TRIM5α domains mediate TAB2 level effects, NF-κB activation, and capsid recognition independently.","method":"Co-immunoprecipitation, Western blot for TAB2 levels, NF-κB reporter assay, domain deletion/swap analysis","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and domain mapping, single lab; consistent with independently described NF-κB/TAK1 activation role","pmids":["21035162"],"is_preprint":false},{"year":2011,"finding":"SUMO-interacting motifs (SIMs) in the TRIM5α B30.2 domain are required for its anti-N-MLV activity; SUMO-1 overexpression blocks N-MLV infection in a TRIM5α-dependent manner; SUMO conjugation of the MLV capsid CA is also required for TRIM5α restriction, suggesting TRIM5α binds SUMO-conjugated CA via its SIMs.","method":"SUMO-1 overexpression, TRIM5α knockdown rescue, SIM mutagenesis, Ub/SUMO conjugation site mutation of CA, retroviral infectivity assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of both TRIM5α SIMs and CA SUMO sites, single lab; novel mechanism not independently confirmed","pmids":["21490953"],"is_preprint":false},{"year":2010,"finding":"p62/sequestosome-1 co-localizes with TRIM5α cytoplasmic bodies, closely associates with TRIM5α as shown by FRET, and sustains TRIM5α protein expression and cytoplasmic body number; p62 knockdown reduces TRIM5α-mediated retroviral restriction in both overexpressing and endogenous TRIM5α-expressing cells.","method":"Co-IP, FRET analysis, siRNA knockdown of p62, retroviral infectivity assays, immunofluorescence","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET plus loss-of-function with functional readout, single lab","pmids":["20357094"],"is_preprint":false},{"year":2015,"finding":"Among seven primate and carnivore TRIM5 orthologs, all activate AP-1 innate immune signaling, and this activation is TAK1-dependent and required for retroviral restriction activity; mouse Trim12 (but not Trim30) paralogs also show this correlation when fused to CypA.","method":"AP-1 reporter assays, TAK1 inhibition, TRIMCyp fusion proteins, retroviral infectivity assays with panel of TRIM5 orthologs","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — panel of orthologs tested with reporter assay and TAK1 inhibition, single lab; corroborates PMID 21512573","pmids":["26468522"],"is_preprint":false},{"year":2015,"finding":"In dendritic cells (DCs), endogenous TRIM5α accumulates in nuclear bodies in a SUMOylation-dependent manner, preventing cytoplasmic retroviral restriction but enabling cGAS-mediated type I IFN sensing of incoming reverse-transcribed DNA. Inhibiting SUMOylation (ginkgolic acid) redistributes TRIM5α to the cytoplasm, restoring restriction but abolishing IFN production.","method":"Immunofluorescence localization of endogenous TRIM5α, SUMOylation inhibitor treatment, cGAS reporter assays, retroviral infectivity assays, primary DC isolation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment tied to functional consequence, pharmacological SUMOylation inhibition, primary cell validation, single lab","pmids":["26748714"],"is_preprint":false},{"year":2019,"finding":"Both human and rhesus TRIM5α restrict specific flaviviruses (tick-borne encephalitis complex) by binding to the viral NS2B/3 protease via the SPRY domain, promoting K48-linked ubiquitination of NS2B/3 and its proteasomal degradation; mosquito-borne flaviviruses (dengue, Zika, yellow fever) are resistant.","method":"Co-IP of TRIM5α with NS2B/3, ubiquitination assays, proteasome inhibitor rescue, retroviral infectivity assays, TRIM5α knockdown","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by co-IP, ubiquitination linked to proteasomal degradation, loss-of-function validation, single lab","pmids":["31189110"],"is_preprint":false},{"year":2020,"finding":"Human TRIM5α senses and restricts LINE-1 retroelements; TRIM5α interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm (required for restriction) and induces AP-1 and NF-κB innate immune signaling upon LINE-1 interaction, leading to down-regulation of LINE-1 promoter activity.","method":"Co-IP of TRIM5α with LINE-1 RNP complexes, LINE-1 retrotransposition reporter assays, siRNA knockdown, AP-1/NF-κB reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and loss-of-function with reporter assays, single lab; novel finding","pmids":["32651277"],"is_preprint":false},{"year":2020,"finding":"TRIM5α self-assembles into hexagonal lattices on HIV-1 capsid; constrained diffusion allows lattice reorganization; defects form on highly curved capsid surfaces to alleviate strain; the TRIM5α binding interface on CA is localized near the CypA-binding loop by statistical analysis of simulation data.","method":"Coarse-grained molecular dynamics simulations validated by electron cryo-tomography imaging","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural/computational method with cryoET validation; binding interface localization is computational inference rather than direct mutagenesis","pmids":["32161265"],"is_preprint":false},{"year":2018,"finding":"TRIM5α binding to HIV-1 capsid induces global rigidification of the capsid assembly and perturbs key inter-molecular interfaces essential for higher-order capsid assembly, with structural and dynamic changes throughout the entire CA polypeptide; this suggests TRIM5α uses allosteric mechanisms to destabilize the capsid lattice.","method":"Magic-angle spinning NMR of assembled capsid with and without TRIM5α, molecular dynamics simulations","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution NMR of capsid assemblies with TRIM5α, combined with MD simulations, single lab","pmids":["30333189"],"is_preprint":false},{"year":2022,"finding":"Pandemic HIV-1(M) has evolved two specific capsid amino acid adaptations that prevent TRIM5 (and cGAS) triggering in myeloid cells; genetic reversal of these adaptations restores TRIM5-mediated antiviral responses; structural analysis by X-ray crystallography identified the capsid differences.","method":"Phylogenetic analysis, X-ray crystallography of HIV capsid variants, retroviral replication assays in myeloid cells, innate immune reporter assays with capsid point mutants","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with functional reversal genetics in relevant cell model, single lab","pmids":["36289397"],"is_preprint":false},{"year":2023,"finding":"TRIM5α restricts orthopoxviruses by binding to the orthopoxvirus capsid protein L3 via its SPRY domain, promoting innate immune activation; vaccinia virus protein C6 antagonizes TRIM5α by binding to its RING domain and inducing proteasome-dependent degradation; CypA is recruited to poxvirus factories via L3 interaction and antagonizes TRIM5α; CsA (by inhibiting CypA) restores TRIM5α-mediated poxvirus restriction.","method":"Co-IP of TRIM5α with L3 and C6, proteasome inhibitor rescue of TRIM5α levels, TRIM5α knockout/knockdown infectivity assays, CsA treatment, cyclosporine derivative antiviral activity assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding (co-IP), loss-of-function, pharmacological rescue, multiple orthogonal methods, single lab","pmids":["37558876"],"is_preprint":false},{"year":2010,"finding":"TRIM5α directly disrupts the structure of preassembled HIV-1 CA-NC cylindrical complexes in vitro; this disruption is correlated with restriction specificity (rhesus TRIM5α and TRIMCyp disrupt; human TRIM5α and TRIMCyp blocked by CsA do not).","method":"Electron microscopy of CA-NC assemblies incubated with cell lysates expressing TRIM5 proteins, CsA inhibition","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct EM visualization of capsid disruption by cell lysate, single lab; uses lysate not pure protein","pmids":["20410272"],"is_preprint":false},{"year":2011,"finding":"TRIM5α modulates isoforms: alternatively spliced TRIM5 isoforms lacking the SPRY domain (TRIM5ι, γ, δ, κ) act as dominant negatives against TRIM5α; specific knockdown of TRIM5ι increases TRIM5α antiviral activity, indicating that endogenous truncated isoforms physiologically reduce TRIM5α function in human cells.","method":"Isoform-specific siRNA knockdown, retroviral infectivity assays, qRT-PCR quantification of isoform ratios","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific knockdown with functional readout, single lab","pmids":["21632761"],"is_preprint":false},{"year":2010,"finding":"The coiled-coil domain of TRIM5α, in addition to mediating oligomerization, conditions the spectrum of antiretroviral specificity; three specific coiled-coil residues (one under positive selection in primates) influence restriction specificity, cooperating with the PRYSPRY domain to determine capsid capture.","method":"Chimeric TRIM5α constructs between human and squirrel monkey, site-directed mutagenesis of coiled-coil residues, retroviral infectivity assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional assays, single lab","pmids":["20219908"],"is_preprint":false}],"current_model":"TRIM5α is a cytoplasmic E3 ubiquitin ligase and pattern recognition receptor that self-assembles into a deformable hexagonal lattice on incoming retroviral capsids via its B-box 2-mediated higher-order oligomerization and B30.2/SPRY domain-mediated direct capsid binding; upon capsid recognition, TRIM5α promotes premature capsid disassembly at inter-hexamer interfaces, synthesizes K63-linked polyubiquitin chains (via Ube2W-initiated monoubiquitination and Ube2N/Ube2V2 chain elongation) to activate TAK1-dependent AP-1 and NF-κB innate immune signaling, and undergoes capsid-triggered proteasomal degradation, collectively blocking retroviral reverse transcription and infection in a species-specific and capsid lattice-dependent manner; its activity is modulated by CypA (shielding HIV-1 in human cells), SUMOylation-dependent nuclear sequestration in dendritic cells, alternative splicing producing dominant-negative isoforms, and interferon-stimulated immunoproteasome activation, while the same SPRY-domain-based mechanism extends to flavivirus protease targeting and poxvirus restriction."},"narrative":{"mechanistic_narrative":"TRIM5α is a cytoplasmic antiretroviral restriction factor and innate immune sensor that recognizes incoming retroviral capsids in a species-specific, capsid-dependent manner and blocks infection at a post-entry, pre-reverse transcription step [PMID:14985764, PMID:15249690, PMID:15249685, PMID:15249687]. Recognition is achieved by direct binding of the C-terminal B30.2/PRY-SPRY domain to the assembled capsid lattice, mediated by hypervariable surface loops including the mobile v1 segment that bind CA assemblies in a manner paralleling antibody antigen recognition [PMID:16540544, PMID:18799573, PMID:22847415, PMID:23091002]. Effective capsid capture requires higher-order self-assembly: TRIM5α dimers oligomerize through B-box 2 (dependent on a hydrophobic surface patch and Arg121) into a deformable hexagonal lattice whose spacing matches the underlying capsid, templated by the CA array [PMID:19656869, PMID:21187419, PMID:27253059]. Engagement of the lattice promotes premature, accelerated capsid disassembly at inter-hexamer interfaces, rigidifying and allosterically destabilizing the CA shell and converting particulate capsid into soluble protein [PMID:16540544, PMID:21455494, PMID:30333189]. TRIM5α is a RING-domain E3 ubiquitin ligase whose activity is potentiated by capsid-induced clustering: RING dimerization activates the K63-specific E2 Ubc13/Uev1A, with Ube2W initiating monoubiquitination and Ube2N/Ube2V2 elongating K63-linked chains, generating unanchored and N-terminally anchored polyubiquitin that activates TAK1-dependent AP-1 and NF-κB signaling and triggers proteasomal turnover of TRIM5α itself [PMID:21512573, PMID:21734049, PMID:26101372, PMID:26212332, PMID:30503508]. Capsid encounter drives rapid proteasome-dependent degradation of TRIM5α, and although the proteasome executes core disruption, restriction can persist when it is inhibited, indicating TRIM5α acts at multiple steps [PMID:16472833, PMID:16973579, PMID:18497858, PMID:23505372]. Its activity is tuned by CypA, which shields HIV-1 from human TRIM5α restriction [PMID:16203999, PMID:31636416], by SUMOylation-dependent nuclear sequestration in dendritic cells that redirects TRIM5α toward cGAS-mediated IFN sensing [PMID:26748714], by interferon induction and immunoproteasome reprogramming [PMID:16289103, PMID:30886358], and by dominant-negative spliced isoforms lacking the SPRY domain [PMID:21632761]. In owl and pigtailed macaques, retrotransposition of CypA into the TRIM5 locus generated TRIMCyp fusions with CypA-dependent capsid recognition [PMID:15243629, PMID:15326303, PMID:18287034, PMID:18389077]. The same SPRY-based recognition extends restriction beyond retroviruses to tick-borne flavivirus NS2B/3 protease, orthopoxvirus L3 capsid protein, and LINE-1 retroelements [PMID:31189110, PMID:37558876, PMID:32651277].","teleology":[{"year":2004,"claim":"Established that a host factor blocks retroviruses after entry but before reverse transcription, defining TRIM5α as the species-specific capsid-acting restriction factor.","evidence":"siRNA knockdown and retroviral infectivity assays in Old World monkey cells; ortholog overexpression with capsid mutants","pmids":["14985764","15249690","15249685","15249687"],"confidence":"High","gaps":["Molecular basis of capsid recognition not yet defined","Mechanism downstream of recognition unknown"]},{"year":2004,"claim":"Showed that capsid recognition can be repurposed through a CypA fusion, establishing the modular nature of the recognition determinant via the natural TRIMCyp fusion.","evidence":"cDNA cloning, RNAi, functional transfer to human/rat cells, cyclosporin A inhibition in owl monkey cells","pmids":["15243629","15326303"],"confidence":"High","gaps":["Did not address whether endogenous CypA modulates native TRIM5α","Convergent independent fusions not yet known"]},{"year":2005,"claim":"Defined TRIM5α oligomerization and identified that CypA acts upstream of TRIM5α, and that interferon transcriptionally induces TRIM5α.","evidence":"Analytical ultracentrifugation, co-IP, dominant-negative assays; dual RNAi epistasis; ISRE reporter and EMSA","pmids":["16254380","15919943","16203999","16289103","16183097"],"confidence":"Medium","gaps":["Oligomeric state later revised to predominantly dimeric","Mechanism of CypA shielding not resolved at this stage"]},{"year":2006,"claim":"Demonstrated that direct B30.2-mediated capsid binding drives accelerated, premature uncoating, separating capsid disassembly from proteasome-dependent steps and showing restriction acts at multiple stages.","evidence":"Capsid binding and particulate/soluble CA assays, domain and capsid mutants, proteasome inhibitor with qPCR for RT products and in vitro integration","pmids":["16540544","17135314","16973579","16472833"],"confidence":"High","gaps":["Did not establish the enzymatic basis of restriction","Relationship between uncoating and signaling unresolved"]},{"year":2008,"claim":"Reconstituted TRIM5α E3 ubiquitin ligase activity and direct SPRY-mediated capsid binding with pure recombinant protein, proving the activities are intrinsic and require no other mammalian factors.","evidence":"Analytical ultracentrifugation, in vitro auto-ubiquitylation with multiple E2s, direct CA-NC binding via SPRY V1 loop; capsid-triggered degradation across restrictive pairs","pmids":["18799573","18312418","18497858","18287034","18389077"],"confidence":"High","gaps":["Ubiquitin chain linkage type not yet defined","Physiological E2 partner not identified"]},{"year":2009,"claim":"Resolved the B-box 2 structure and showed it drives higher-order self-association and avid capsid binding, identifying the assembly module underlying potent restriction.","evidence":"NMR structure of B-box 2, mutagenesis (cluster 1 patch, Arg121), capsid binding and infectivity assays","pmids":["19656869"],"confidence":"High","gaps":["Lattice geometry not directly visualized","Link between assembly and enzymatic output unestablished"]},{"year":2010,"claim":"Visualized TRIM5α self-assembly into hexagonal lattices templated by capsid arrays and showed direct in vitro capsid disruption, framing the deformable scaffold model of recognition.","evidence":"EM of 2D paracrystalline arrays with mutagenesis; EM of CA-NC disruption by lysate; coiled-coil specificity mutagenesis; live-cell imaging of cytoplasmic bodies; p62 dependency","pmids":["21187419","20410272","20219908","17392513","20357094","21035162"],"confidence":"High","gaps":["Lattice assembly studied largely in vitro","Cytoplasmic body function dissociated from restriction but role unclear"]},{"year":2011,"claim":"Identified the K63-ubiquitin/TAK1 signaling axis and the structural basis of capsid disruption at inter-hexamer interfaces, unifying restriction and innate immune activation.","evidence":"In vitro K63 chain synthesis with UBC13-UEV1A, TAK1/UBC13 knockdown, NF-κB/AP-1 reporters; cryoEM and crosslinking of CA disruption; RING NMR structure with mutagenesis; SIM-dependent SUMO mechanism; isoform dominant negatives","pmids":["21512573","21455494","21734049","21490953","21632761"],"confidence":"High","gaps":["Order of monoubiquitination versus chain elongation not resolved","Substrate of K63 signaling versus auto-modification unclear"]},{"year":2012,"claim":"Determined the PRY/SPRY crystal structure, establishing that flexible hypervariable loops on a divergent face mediate capsid recognition akin to antibody antigen binding.","evidence":"X-ray crystallography of rhesus PRY/SPRY with biochemical CA binding and cryoEM","pmids":["22847415","23091002"],"confidence":"High","gaps":["Affinity of monomeric versus assembled binding not quantified","Determinants of species specificity at residue level incompletely mapped"]},{"year":2015,"claim":"Defined the E2 enzyme cascade and the requirement of RING dimerization for K63 chain synthesis, linking capsid-induced higher-order assembly to enhanced E3 activity.","evidence":"In vitro ubiquitination reconstitution, E2 depletion, MS site mapping; crystal structure of RING:Ubc13-Ub with ultracentrifugation; AP-1/TAK1 ortholog panel","pmids":["26101372","26212332","26468522"],"confidence":"High","gaps":["In-cell stoichiometry of RING dimerization not directly measured","Coupling of signaling to capsid disruption unresolved"]},{"year":2016,"claim":"Resolved how B-box 2 trimers build the hexagonal net and sterically modulate RING dimerization, and revealed cell-type-specific routing of TRIM5α via Langerin in Langerhans cells.","evidence":"X-ray crystallography of B-box 2 with functional mutagenesis; siRNA, co-IP with Langerin/DC-SIGN, autophagy assays in primary DCs; CRISPR/siRNA showing autophagy dispensable for restriction","pmids":["27253059","27919079","26764007","26748714"],"confidence":"High","gaps":["Whether autophagy contributes context-dependently remains conflicting (compare #31)","Mechanism of Langerin-directed routing incompletely defined"]},{"year":2018,"claim":"Showed that lattice assembly triggers N-terminally anchored K63 chains that drive both signaling and degradation, with premature ubiquitination ablating restriction, establishing assembly-gated control of effector output.","evidence":"MS ubiquitin chain mapping, Ub mutant constructs, inducible ubiquitination, immune reporters; MAS-NMR showing capsid rigidification by TRIM5α","pmids":["30503508","30333189"],"confidence":"High","gaps":["In vivo readers of N-K63-Ub not identified","Quantitative link between rigidification and disassembly unresolved"]},{"year":2019,"claim":"Resolved the long-standing question of human TRIM5α potency by showing CypA shields HIV-1 and that immunoproteasome reprogramming converts human TRIM5α into a potent restrictor.","evidence":"CRISPR/siRNA in primary cells, CA-CypA mutant viruses, core co-fractionation; IFN-α siRNA screen with immunoproteasome subunit depletion; flavivirus NS2B/3 targeting by co-IP and ubiquitination","pmids":["31636416","30886358","31189110"],"confidence":"High","gaps":["How immunoproteasome turnover mechanistically switches activity not fully defined","Breadth of flavivirus substrate specificity limited to tick-borne complex"]},{"year":2020,"claim":"Extended TRIM5α function to LINE-1 retroelement sensing and refined the lattice model with simulation, mapping the CA binding interface near the CypA loop.","evidence":"Co-IP with LINE-1 RNPs, retrotransposition and immune reporters; coarse-grained MD validated by cryoET","pmids":["32651277","32161265"],"confidence":"Medium","gaps":["LINE-1 RNP recognition determinant not structurally defined","Binding interface localization by simulation lacks direct mutagenesis"]},{"year":2022,"claim":"Demonstrated that pandemic HIV-1 evolved specific capsid adaptations that evade TRIM5 triggering, showing the host-pathogen arms race at the structural level.","evidence":"Phylogenetics, X-ray crystallography of capsid variants, reversal genetics in myeloid cells with immune reporters","pmids":["36289397"],"confidence":"High","gaps":["Whether other lentiviral lineages use the same evasion strategy unknown","Structural basis of evasion at the TRIM5 interface incompletely mapped"]},{"year":2023,"claim":"Established TRIM5α as a poxvirus restriction factor with a dedicated viral antagonist, broadening its antiviral scope beyond retroelements and RNA viruses.","evidence":"Co-IP with orthopoxvirus L3 and vaccinia C6, proteasome rescue, TRIM5α knockout infectivity, CsA and cyclosporine derivative assays","pmids":["37558876"],"confidence":"High","gaps":["Whether L3 forms a lattice-like ligand is unknown","Generality of poxvirus restriction across orthopoxvirus species untested"]},{"year":null,"claim":"How TRIM5α-generated polyubiquitin signals are decoded by downstream effectors in vivo, and how a single SPRY-based recognition module is tuned to such diverse ligands (retroviral lattices, flavivirus protease, poxvirus capsid, LINE-1 RNPs), remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Ubiquitin chain readers downstream of TRIM5α not identified","Unifying determinants of broad SPRY ligand specificity unresolved","Physiological contribution of nuclear/IFN-sensing versus cytoplasmic restriction in vivo unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[8,9,13,15,24,25,28]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[13,24,38]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,33,36,39]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,3,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11,12,26]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,9,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[37]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,36,37,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,38,43]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,33,36]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[24,28,38,43]}],"complexes":["TRIM5α hexagonal capsid-templated lattice"],"partners":["CYPA","UBE2N/UBC13","UBE2V2/UEV1A","UBE2W","TAK1","LANGERIN","P62/SQSTM1","TAB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C035","full_name":"Tripartite motif-containing protein 5","aliases":["RING finger protein 88","RING-type E3 ubiquitin transferase TRIM5"],"length_aa":493,"mass_kda":56.3,"function":"Capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses. Blocks viral replication early in the life cycle, after viral entry but before reverse transcription. In addition to acting as a capsid-specific restriction factor, also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Binding to the viral capsid triggers its E3 ubiquitin ligase activity, and in concert with the heterodimeric ubiquitin conjugating enzyme complex UBE2V1-UBE2N (also known as UBC13-UEV1A complex) generates 'Lys-63'-linked polyubiquitin chains, which in turn are catalysts in the autophosphorylation of the MAP3K7/TAK1 complex (includes TAK1, TAB2, and TAB3). Activation of the MAP3K7/TAK1 complex by autophosphorylation results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes, thereby leading to an innate immune response in the infected cell. Restricts infection by N-tropic murine leukemia virus (N-MLV), equine infectious anemia virus (EIAV), simian immunodeficiency virus of macaques (SIVmac), feline immunodeficiency virus (FIV), and bovine immunodeficiency virus (BIV) (PubMed:17156811). Plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2 (PubMed:25127057). Also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction (PubMed:25127057)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9C035/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM5","total_profiled":1310},"omim":[{"mim_id":"608531","title":"BTB/POZ DOMAIN-CONTAINING PROTEIN 2; BTBD2","url":"https://www.omim.org/entry/608531"},{"mim_id":"608530","title":"BTB/POZ DOMAIN-CONTAINING PROTEIN 1; BTBD1","url":"https://www.omim.org/entry/608530"},{"mim_id":"608487","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 5; TRIM5","url":"https://www.omim.org/entry/608487"},{"mim_id":"607564","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 6; TRIM6","url":"https://www.omim.org/entry/607564"},{"mim_id":"603679","title":"UBIQUITIN-CONJUGATING ENZYME E2 N; UBE2N","url":"https://www.omim.org/entry/603679"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM5"},"hgnc":{"alias_symbol":["RNF88","TRIM5alpha"],"prev_symbol":[]},"alphafold":{"accession":"Q9C035","domains":[{"cath_id":"3.30.40.10","chopping":"2-70","consensus_level":"high","plddt":85.1625,"start":2,"end":70},{"cath_id":"2.60.120.920","chopping":"297-489","consensus_level":"high","plddt":83.5008,"start":297,"end":489},{"cath_id":"3.90.20","chopping":"173-269","consensus_level":"high","plddt":91.7723,"start":173,"end":269}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C035","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C035-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C035-F1-predicted_aligned_error_v6.png","plddt_mean":85.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM5","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM5"},"sequence":{"accession":"Q9C035","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C035.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C035/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C035"}},"corpus_meta":[{"pmid":"14985764","id":"PMC_14985764","title":"The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14985764","citation_count":1529,"is_preprint":false},{"pmid":"16540544","id":"PMC_16540544","title":"Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16540544","citation_count":616,"is_preprint":false},{"pmid":"15243629","id":"PMC_15243629","title":"Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15243629","citation_count":550,"is_preprint":false},{"pmid":"21512573","id":"PMC_21512573","title":"TRIM5 is an innate immune sensor for the retrovirus capsid 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cytoplasmic bodies) restricts HIV-1 infection in Old World monkey cells at a post-entry, pre-reverse transcription step; the block is species-specific, acts on the incoming viral capsid, and is relieved by TRIM5α knockdown.\",\n      \"method\": \"siRNA knockdown, retroviral infectivity assays, subcellular localization by immunofluorescence\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function (siRNA) with defined cellular phenotype, replicated across multiple labs in the same year\",\n      \"pmids\": [\"14985764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRIM5α restricts both HIV-1 and N-tropic murine leukemia virus (N-MLV), indicating broader antiretroviral specificity determined by the viral capsid; human, rhesus, and African green monkey TRIM5α variants show different but overlapping restriction spectra.\",\n      \"method\": \"Overexpression of TRIM5α orthologs in permissive cells, retroviral infectivity assays with capsid mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthologs tested with panel of capsid mutants, replicated independently\",\n      \"pmids\": [\"15249690\", \"15249685\", \"15249687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In owl monkeys, a LINE-1 retrotransposon-mediated insertion of a CypA cDNA into the TRIM5 locus creates a TRIM5-CypA fusion protein (TRIMCyp) that restricts HIV-1 through CypA-dependent capsid recognition; this fusion accounts for post-entry HIV-1 restriction in owl monkey cells.\",\n      \"method\": \"RNAi knockdown, cDNA cloning, transfer of TRIMCyp to human/rat cells, cyclosporin A inhibition assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi, functional transfer, pharmacological inhibition; independently confirmed by multiple labs\",\n      \"pmids\": [\"15243629\", \"15326303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRIM5α orthologs from Old World monkeys specifically associate with the HIV-1 capsid via the B30.2 domain; this interaction promotes rapid, premature capsid disassembly (accelerated uncoating) as shown by loss of particulate capsid and gain of soluble capsid protein. Proteasome inhibition does not abrogate restriction.\",\n      \"method\": \"Capsid binding assays, quantification of particulate vs. soluble capsid after infection, proteasome inhibitor treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct capsid binding assay plus biochemical uncoating readout, replicated in multiple TRIM5 variants\",\n      \"pmids\": [\"16540544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human TRIM5α mediates accelerated uncoating (premature conversion of particulate to soluble capsid) of N-MLV in a capsid residue 110-dependent manner; domains required for potent restriction are also required for capsid disassembly.\",\n      \"method\": \"Quantification of particulate vs. soluble MLV capsid in infected cells, domain deletion mutants, capsid residue 110 mutants\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical capsid disassembly assay with domain mutants and viral capsid mutants, single lab\",\n      \"pmids\": [\"17135314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRIM5α is rapidly turned over (half-life ~50–60 min) via polyubiquitylation dependent on intact RING and B-box 2 domains; proteasome inhibition triggers aggresome formation containing TRIM5α, polyubiquitylated proteins, heat shock proteins, and dynein.\",\n      \"method\": \"Pulse-chase half-life assays, domain mutant analysis, proteasome inhibitor treatment, immunofluorescence co-localization\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase, domain mutants, pharmacological inhibition with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"16472833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Proteasome inhibition of TRIM5α-restricted cells allows reverse transcription products to accumulate even though infection remains blocked, indicating TRIM5α restricts retroviral infection at multiple steps; pre-integration complexes generated under proteasome inhibition are competent for integration in vitro.\",\n      \"method\": \"Proteasome inhibitor treatment, quantitative PCR for reverse transcription products, in vitro integration assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple TRIM5 variants tested, in vitro integration assay, replicated across multiple restriction factors\",\n      \"pmids\": [\"16973579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM5α oligomerizes into trimers; the coiled-coil and B30.2(SPRY) domains contribute to trimer formation/stability. A RING/B-box 2-deleted dominant-negative TRIM5α forms heterotrimers with wild-type TRIM5α, explaining the dominant-negative effect.\",\n      \"method\": \"Analytical ultracentrifugation, co-immunoprecipitation, gel filtration, dominant-negative assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biophysical methods but later work shows dimers are the predominant species; single lab\",\n      \"pmids\": [\"16254380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Recombinant TRIM5α (TRIM5-21R chimera) is predominantly dimeric; it has E3 ubiquitin ligase activity (auto-ubiquitylation with multiple E2 enzymes in vitro) and directly binds HIV-1 CA-NC assemblies via the SPRY domain V1 loop without other mammalian proteins.\",\n      \"method\": \"Analytical ultracentrifugation, in vitro ubiquitylation assay, direct capsid binding assay with purified recombinant protein\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of E3 ligase activity and direct capsid binding with pure recombinant protein, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18799573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM5α functions as a RING-finger E3 ubiquitin ligase in vitro and in vivo, auto-ubiquitinates in cooperation with UbcH5B, is also ubiquitinated by Ro52 (another E3 ligase), and deubiquitinated by Yersinia effector YopJ. Monoubiquitination of TRIM5α signals its translocation from cytoplasmic bodies to the cytoplasm.\",\n      \"method\": \"In vitro ubiquitylation assay, overexpression/co-IP, monoubiquitin-fusion assay, confocal microscopy\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro E3 assay plus cellular localization assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18312418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Encounter with a restriction-sensitive retroviral core causes rapid proteasome-dependent degradation of TRIM5α; this occurs specifically with restrictive TRIM5α-capsid pairs (rhesus TRIM5α with HIV-1, human TRIM5α with N-MLV, TRIMCyp with HIV-1) and is prevented by proteasome inhibitors or CsA.\",\n      \"method\": \"Western blot of TRIM5α levels after virus inoculation, proteasome inhibitor treatment, CsA treatment, endogenous TRIM5α measurement in rhesus cells\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple restriction factor/virus pairs tested, endogenous protein measured, pharmacological controls, single lab with strong internal replication\",\n      \"pmids\": [\"18497858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The TRIM5α B-box 2 domain has an unusual hydrophobic surface patch (cluster 1) and flanking Arg121 that are required for higher-order self-association and avid capsid binding, which are the major mechanisms by which B-box 2 potentiates HIV-1 restriction (not turnover or cytoplasmic body formation).\",\n      \"method\": \"NMR structure of B-box 2 domain, site-directed mutagenesis, capsid binding assays, higher-order oligomerization assays, retroviral infectivity assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure combined with mutagenesis and functional assays, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"19656869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Recombinant TRIM5α spontaneously assembles into two-dimensional paracrystalline hexagonal lattices; assembly requires protein dimerization and B-box 2 Arg121 but not the SPRY domain. Assembly is promoted by binding to hexagonal CA arrays, suggesting a deformable hexagonal scaffold model for retroviral capsid recognition.\",\n      \"method\": \"Electron microscopy of 2D crystalline arrays, mutagenesis, capsid array-templated assembly assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural EM of recombinant protein assemblies with mutagenesis validation, single lab\",\n      \"pmids\": [\"21187419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM5 is a RING domain E3 ubiquitin ligase that, acting with UBC13-UEV1A, catalyses synthesis of unattached K63-linked ubiquitin chains to activate TAK1 kinase and stimulate AP-1 and NF-κB innate immune signalling; interaction with the retroviral capsid lattice greatly enhances UBC13-UEV1A-dependent E3 activity; TAK1 and UBC13 contribute to capsid-specific restriction.\",\n      \"method\": \"In vitro ubiquitin chain synthesis assay, TAK1/UBC13 knockdown, NF-κB/AP-1 reporter assays, virus challenge experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of K63-ubiquitin chain synthesis, multiple loss-of-function approaches, reporter assays, mechanistic epistasis; replicated in subsequent studies\",\n      \"pmids\": [\"21512573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rhesus TRIM5α disrupts the HIV-1 capsid specifically at inter-hexamer interfaces; CC-SPRY domain binds CA assemblies in a concentration-dependent manner and releases protofilament fragments of CA hexamers without dissociating into monomers. Intra-hexamer crosslinking does not prevent disruption, but inter-hexamer crosslinking does.\",\n      \"method\": \"CryoEM of CA assemblies incubated with purified TRIM5α fragments, chemical crosslinking with disulfide bond-forming CA mutants\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryoEM structural analysis combined with mutagenesis and crosslinking, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21455494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The RING domain of TRIM5α has E3 ubiquitin ligase activity; RING domain residues in the E2-binding region are required for both self-ubiquitylation and potent HIV-1 restriction, demonstrating that E3 ligase activity contributes to restriction. The NMR structure of the TRIM5α RING domain was determined.\",\n      \"method\": \"NMR structure determination, site-directed mutagenesis of RING domain, in vitro self-ubiquitylation assay, retroviral infectivity assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure, systematic mutagenesis, in vitro E3 assay linked to functional restriction, single lab\",\n      \"pmids\": [\"21734049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the rhesus TRIM5α PRY/SPRY domain reveals that capsid binding is mediated by flexible hypervariable loops (including the mobile v1 segment) that map to the structurally divergent face, paralleling antigen recognition by IgM antibodies; the monomeric PRY/SPRY alone can bind HIV-1 CA assemblies.\",\n      \"method\": \"X-ray crystallography of PRY/SPRY domain, biochemical capsid binding assay, cryoEM\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent crystal structures (two papers) with biochemical binding validation\",\n      \"pmids\": [\"22847415\", \"23091002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CypA is required for HIV-1 restriction by Old World monkey TRIM5α: CypA knockdown increases HIV-1 infectivity to the same extent as TRIM5 knockdown; CsA and CA mutations that disrupt CypA binding rescue HIV-1 from restriction; simultaneous CypA and TRIM5 knockdown causes no additional increase in titer, placing CypA upstream of TRIM5α.\",\n      \"method\": \"RNAi knockdown of CypA and TRIM5 (separately and combined), CsA treatment, CA mutant viruses, epistasis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via dual RNAi knockdown, pharmacological inhibition, viral capsid mutants; replicated by multiple labs\",\n      \"pmids\": [\"16203999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM5α orthologs form heteromultimers via their conserved coiled-coil domains; non-human primate TRIM5α expressed in human cells can disrupt the anti-N-MLV activity of endogenous human TRIM5α through heteromultimerization, not through the C-terminal capsid-recognition domain.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative assays, co-localization, domain deletion analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional dominant-negative assay with domain deletions, single lab\",\n      \"pmids\": [\"15919943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRIM5α cytoplasmic bodies are highly dynamic structures: they move along microtubules (saltatory and long-distance), undergo morphological changes, and TRIM5α protein rapidly exchanges between cytoplasmic bodies and diffuse cytoplasmic pools. Association with cytoplasmic bodies is not required for antiretroviral activity.\",\n      \"method\": \"Live-cell fluorescence microscopy, FRAP, photoactivation, microtubule perturbation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging, FRAP, and photoactivation with functional correlation; single lab, multiple orthogonal live-cell methods\",\n      \"pmids\": [\"17392513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cytoplasmic body association is not required for TRIM5α antiretroviral activity: spider monkey TRIM5α restricts retroviruses without forming cytoplasmic bodies; geldanamycin (Hsp90 inhibitor) dissolves cytoplasmic bodies without affecting restriction.\",\n      \"method\": \"Overexpression of TRIM5α orthologs (GFP fusion), geldanamycin treatment, retroviral infectivity assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological disruption plus natural variant lacking bodies, single lab\",\n      \"pmids\": [\"16183097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM5α transcription is upregulated by interferons (IFN-α and IFN-β) through an ISRE element in the TRIM5α promoter; STAT1 binds to the ISRE sequence; IFN-β induces TRIM5α protein expression.\",\n      \"method\": \"Northern blot, qRT-PCR, luciferase reporter assay, EMSA, Western blot with specific antibody\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transcriptional assays with EMSA and mutational analysis of ISRE, single lab\",\n      \"pmids\": [\"16289103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A second, independently generated TRIM5-CypA fusion (TRIMCyp) exists in pigtailed macaques; its distinct HIV-1 restriction specificity is explained by a point mutation near the CypA:capsid-binding interface acquired during/after transposition.\",\n      \"method\": \"Genomic sequencing, functional infectivity assays, CsA inhibition, site-directed mutagenesis of CypA interface\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — convergent evolutionary example confirmed functionally with mutagenesis, independently reported by two groups\",\n      \"pmids\": [\"18287034\", \"18389077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"When MLV infection is restricted by human TRIM5α, integrase protein and reverse transcription products are lost from cells while capsid and viral RNA are solubilized; proteasome inhibition blocks these biochemical consequences but not antiviral potency, indicating proteasomes are required for TRIM5α-induced core disruption but not restriction per se.\",\n      \"method\": \"Sucrose gradient fractionation of retroviral core components after synchronized infection, proteasome inhibitor treatment, quantitative detection of CA, integrase, viral RNA, and RT products\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel biochemical fractionation assay tracking multiple core components, pharmacological dissection of restriction steps, single lab\",\n      \"pmids\": [\"23505372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM5α employs E2 enzyme Ube2W to anchor K63-linked polyubiquitin chains via TRIM5α auto-ubiquitination; Ube2W monoubiquitinates TRIM5α at internal lysines (especially K45 and K50), which serves as a substrate for chain elongation by Ube2N/Ube2V2; depletion of these E2 enzymes or ubiquitin mutation inhibits restriction-associated reverse transcription block.\",\n      \"method\": \"In vitro ubiquitination reconstitution, E2 depletion by siRNA, Ub mutant analysis, MS identification of modified lysines\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus cellular loss-of-function with MS identification of modification sites, single lab\",\n      \"pmids\": [\"26101372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RING dimerization of TRIM5α is required for activation of Ubc13 (K63-linkage-specific E2) to synthesize K63-linked polyubiquitin chains; higher-order oligomerization (promoted by capsid interaction) enhances RING dimerization and therefore E3 ligase activity.\",\n      \"method\": \"Crystal structure of TRIM5α RING:Ubc13-Ub complex, analytical ultracentrifugation, mutagenesis, in vitro ubiquitination assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical reconstitution and mutagenesis validation, single lab\",\n      \"pmids\": [\"26212332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the TRIM5α B-box 2 domain shows it can form both dimers and trimers; trimers link multiple TRIM5α proteins into a hexagonal net matching capsid lattice spacing. B-box-mediated interactions also sterically restrict RING domain dimerization, modulating E3 ligase activity.\",\n      \"method\": \"X-ray crystallography, functional mutagenesis, capsid binding and restriction assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mutagenesis and mechanistic linkage to E3 activity, single lab\",\n      \"pmids\": [\"27253059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human TRIM5α restricts HIV-1 in Langerhans cells (LCs) but not in subepithelial DC-SIGN+ DCs; restriction depends on HIV-1 binding to Langerin (C-type lectin), which routes HIV-1 into a TRIM5α-mediated autophagy-activating pathway; DC-SIGN binding causes TRIM5α to dissociate and abrogates restriction.\",\n      \"method\": \"siRNA knockdown of TRIM5α in primary DCs, co-IP of TRIM5α with Langerin/DC-SIGN, autophagy inhibitor assays, confocal microscopy, retroviral infectivity assays in primary cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, co-IP, pharmacological inhibition) in primary human cells, single lab\",\n      \"pmids\": [\"27919079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hexagonal assembly of TRIM5 on retroviral capsids triggers N-terminal polyubiquitination; trivalent RING arrangement enables elongation of N-terminally anchored K63-linked ubiquitin chains (N-K63-Ub). N-K63-Ub drives innate immune stimulation and proteasomal degradation of TRIM5; premature ubiquitination before lattice assembly triggers degradation and ablates restriction.\",\n      \"method\": \"Ubiquitin chain analysis by MS, Ub mutant TRIM5α constructs, inducible ubiquitination system, innate immune reporter assays, retroviral infectivity assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-based ubiquitin chain mapping, mechanistic dissection with multiple Ub mutants and inducible systems, single lab\",\n      \"pmids\": [\"30503508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CypA shields HIV-1 from restriction by human TRIM5α in primary human blood cells; disruption of the CA-CypA interaction renders HIV-1 susceptible to potent human TRIM5α restriction before reverse transcription; endogenous TRIM5α associates with virion cores entering the cytoplasm only when the CA-CypA interaction is disrupted.\",\n      \"method\": \"CRISPR/CAS9 knockout and siRNA knockdown of TRIM5α in primary cells, CA-CypA mutant viruses, CsA treatment, co-fractionation of TRIM5α with incoming cores\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — primary cell gene editing, biochemical fractionation, CA mutants, pharmacological controls; definitively resolves longstanding question\",\n      \"pmids\": [\"31636416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Immunoproteasome activation (by IFN-α) reprograms human TRIM5α for effective capsid-dependent HIV-1 restriction; the immunoproteasome accelerates TRIM5α turnover, and this is required for the switch to potent anti-HIV-1 activity; restriction is dependent on viral capsid.\",\n      \"method\": \"siRNA library screen in IFN-α-treated cells, siRNA/CRISPR knockdown of immunoproteasome subunits, HIV-1 infectivity assays, TRIM5α stability measurements\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased screen followed by mechanistic validation with multiple loss-of-function approaches, single lab\",\n      \"pmids\": [\"30886358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM5α acts as a selective autophagy receptor for HIV-1; it recognizes and targets HIV-1 for autophagic destruction and nucleates the core autophagy machinery by assembling ULK1 and BECN1 into an active complex; TRIM5α interactions with mammalian Atg8 proteins are required for this anti-HIV effector function.\",\n      \"method\": \"Co-IP of TRIM5α with autophagy components, knockdown of autophagic mediators, retroviral infectivity assays, protein interaction mapping\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and knockdown data, but subsequent study (PMID 26764007) found autophagy not required for restriction; conflicting results lower confidence\",\n      \"pmids\": [\"25587751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Autophagic degradation of TRIM5α occurs basally (LC3b and LAMP2A co-localize with TRIM5α bodies); however, depletion of ATG5, Beclin1, or p62 by siRNA or CRISPR does not abrogate retroviral restriction by human TRIM5α, rhesus TRIM5α, or TRIMCyp, indicating autophagy is not required for restriction.\",\n      \"method\": \"siRNA and CRISPR-Cas9 depletion of autophagy mediators, retroviral infectivity assays, immunofluorescence co-localization, lysosomal inhibitor treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR and siRNA with multiple autophagy targets, multiple TRIM5 orthologs tested; NEGATIVE finding for autophagy requirement is well-supported\",\n      \"pmids\": [\"26764007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human TRIM5α affects TAB2 protein levels, abrogating TAB2-dependent NF-κB activation; human and rhesus TRIM5α also activate NF-κB reporter expression in a dose-dependent manner; distinct TRIM5α domains mediate TAB2 level effects, NF-κB activation, and capsid recognition independently.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for TAB2 levels, NF-κB reporter assay, domain deletion/swap analysis\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and domain mapping, single lab; consistent with independently described NF-κB/TAK1 activation role\",\n      \"pmids\": [\"21035162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SUMO-interacting motifs (SIMs) in the TRIM5α B30.2 domain are required for its anti-N-MLV activity; SUMO-1 overexpression blocks N-MLV infection in a TRIM5α-dependent manner; SUMO conjugation of the MLV capsid CA is also required for TRIM5α restriction, suggesting TRIM5α binds SUMO-conjugated CA via its SIMs.\",\n      \"method\": \"SUMO-1 overexpression, TRIM5α knockdown rescue, SIM mutagenesis, Ub/SUMO conjugation site mutation of CA, retroviral infectivity assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of both TRIM5α SIMs and CA SUMO sites, single lab; novel mechanism not independently confirmed\",\n      \"pmids\": [\"21490953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p62/sequestosome-1 co-localizes with TRIM5α cytoplasmic bodies, closely associates with TRIM5α as shown by FRET, and sustains TRIM5α protein expression and cytoplasmic body number; p62 knockdown reduces TRIM5α-mediated retroviral restriction in both overexpressing and endogenous TRIM5α-expressing cells.\",\n      \"method\": \"Co-IP, FRET analysis, siRNA knockdown of p62, retroviral infectivity assays, immunofluorescence\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus loss-of-function with functional readout, single lab\",\n      \"pmids\": [\"20357094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Among seven primate and carnivore TRIM5 orthologs, all activate AP-1 innate immune signaling, and this activation is TAK1-dependent and required for retroviral restriction activity; mouse Trim12 (but not Trim30) paralogs also show this correlation when fused to CypA.\",\n      \"method\": \"AP-1 reporter assays, TAK1 inhibition, TRIMCyp fusion proteins, retroviral infectivity assays with panel of TRIM5 orthologs\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — panel of orthologs tested with reporter assay and TAK1 inhibition, single lab; corroborates PMID 21512573\",\n      \"pmids\": [\"26468522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In dendritic cells (DCs), endogenous TRIM5α accumulates in nuclear bodies in a SUMOylation-dependent manner, preventing cytoplasmic retroviral restriction but enabling cGAS-mediated type I IFN sensing of incoming reverse-transcribed DNA. Inhibiting SUMOylation (ginkgolic acid) redistributes TRIM5α to the cytoplasm, restoring restriction but abolishing IFN production.\",\n      \"method\": \"Immunofluorescence localization of endogenous TRIM5α, SUMOylation inhibitor treatment, cGAS reporter assays, retroviral infectivity assays, primary DC isolation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment tied to functional consequence, pharmacological SUMOylation inhibition, primary cell validation, single lab\",\n      \"pmids\": [\"26748714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Both human and rhesus TRIM5α restrict specific flaviviruses (tick-borne encephalitis complex) by binding to the viral NS2B/3 protease via the SPRY domain, promoting K48-linked ubiquitination of NS2B/3 and its proteasomal degradation; mosquito-borne flaviviruses (dengue, Zika, yellow fever) are resistant.\",\n      \"method\": \"Co-IP of TRIM5α with NS2B/3, ubiquitination assays, proteasome inhibitor rescue, retroviral infectivity assays, TRIM5α knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by co-IP, ubiquitination linked to proteasomal degradation, loss-of-function validation, single lab\",\n      \"pmids\": [\"31189110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human TRIM5α senses and restricts LINE-1 retroelements; TRIM5α interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm (required for restriction) and induces AP-1 and NF-κB innate immune signaling upon LINE-1 interaction, leading to down-regulation of LINE-1 promoter activity.\",\n      \"method\": \"Co-IP of TRIM5α with LINE-1 RNP complexes, LINE-1 retrotransposition reporter assays, siRNA knockdown, AP-1/NF-κB reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and loss-of-function with reporter assays, single lab; novel finding\",\n      \"pmids\": [\"32651277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM5α self-assembles into hexagonal lattices on HIV-1 capsid; constrained diffusion allows lattice reorganization; defects form on highly curved capsid surfaces to alleviate strain; the TRIM5α binding interface on CA is localized near the CypA-binding loop by statistical analysis of simulation data.\",\n      \"method\": \"Coarse-grained molecular dynamics simulations validated by electron cryo-tomography imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural/computational method with cryoET validation; binding interface localization is computational inference rather than direct mutagenesis\",\n      \"pmids\": [\"32161265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM5α binding to HIV-1 capsid induces global rigidification of the capsid assembly and perturbs key inter-molecular interfaces essential for higher-order capsid assembly, with structural and dynamic changes throughout the entire CA polypeptide; this suggests TRIM5α uses allosteric mechanisms to destabilize the capsid lattice.\",\n      \"method\": \"Magic-angle spinning NMR of assembled capsid with and without TRIM5α, molecular dynamics simulations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution NMR of capsid assemblies with TRIM5α, combined with MD simulations, single lab\",\n      \"pmids\": [\"30333189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pandemic HIV-1(M) has evolved two specific capsid amino acid adaptations that prevent TRIM5 (and cGAS) triggering in myeloid cells; genetic reversal of these adaptations restores TRIM5-mediated antiviral responses; structural analysis by X-ray crystallography identified the capsid differences.\",\n      \"method\": \"Phylogenetic analysis, X-ray crystallography of HIV capsid variants, retroviral replication assays in myeloid cells, innate immune reporter assays with capsid point mutants\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with functional reversal genetics in relevant cell model, single lab\",\n      \"pmids\": [\"36289397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM5α restricts orthopoxviruses by binding to the orthopoxvirus capsid protein L3 via its SPRY domain, promoting innate immune activation; vaccinia virus protein C6 antagonizes TRIM5α by binding to its RING domain and inducing proteasome-dependent degradation; CypA is recruited to poxvirus factories via L3 interaction and antagonizes TRIM5α; CsA (by inhibiting CypA) restores TRIM5α-mediated poxvirus restriction.\",\n      \"method\": \"Co-IP of TRIM5α with L3 and C6, proteasome inhibitor rescue of TRIM5α levels, TRIM5α knockout/knockdown infectivity assays, CsA treatment, cyclosporine derivative antiviral activity assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding (co-IP), loss-of-function, pharmacological rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37558876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIM5α directly disrupts the structure of preassembled HIV-1 CA-NC cylindrical complexes in vitro; this disruption is correlated with restriction specificity (rhesus TRIM5α and TRIMCyp disrupt; human TRIM5α and TRIMCyp blocked by CsA do not).\",\n      \"method\": \"Electron microscopy of CA-NC assemblies incubated with cell lysates expressing TRIM5 proteins, CsA inhibition\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct EM visualization of capsid disruption by cell lysate, single lab; uses lysate not pure protein\",\n      \"pmids\": [\"20410272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM5α modulates isoforms: alternatively spliced TRIM5 isoforms lacking the SPRY domain (TRIM5ι, γ, δ, κ) act as dominant negatives against TRIM5α; specific knockdown of TRIM5ι increases TRIM5α antiviral activity, indicating that endogenous truncated isoforms physiologically reduce TRIM5α function in human cells.\",\n      \"method\": \"Isoform-specific siRNA knockdown, retroviral infectivity assays, qRT-PCR quantification of isoform ratios\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific knockdown with functional readout, single lab\",\n      \"pmids\": [\"21632761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The coiled-coil domain of TRIM5α, in addition to mediating oligomerization, conditions the spectrum of antiretroviral specificity; three specific coiled-coil residues (one under positive selection in primates) influence restriction specificity, cooperating with the PRYSPRY domain to determine capsid capture.\",\n      \"method\": \"Chimeric TRIM5α constructs between human and squirrel monkey, site-directed mutagenesis of coiled-coil residues, retroviral infectivity assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional assays, single lab\",\n      \"pmids\": [\"20219908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM5α is a cytoplasmic E3 ubiquitin ligase and pattern recognition receptor that self-assembles into a deformable hexagonal lattice on incoming retroviral capsids via its B-box 2-mediated higher-order oligomerization and B30.2/SPRY domain-mediated direct capsid binding; upon capsid recognition, TRIM5α promotes premature capsid disassembly at inter-hexamer interfaces, synthesizes K63-linked polyubiquitin chains (via Ube2W-initiated monoubiquitination and Ube2N/Ube2V2 chain elongation) to activate TAK1-dependent AP-1 and NF-κB innate immune signaling, and undergoes capsid-triggered proteasomal degradation, collectively blocking retroviral reverse transcription and infection in a species-specific and capsid lattice-dependent manner; its activity is modulated by CypA (shielding HIV-1 in human cells), SUMOylation-dependent nuclear sequestration in dendritic cells, alternative splicing producing dominant-negative isoforms, and interferon-stimulated immunoproteasome activation, while the same SPRY-domain-based mechanism extends to flavivirus protease targeting and poxvirus restriction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM5α is a cytoplasmic antiretroviral restriction factor and innate immune sensor that recognizes incoming retroviral capsids in a species-specific, capsid-dependent manner and blocks infection at a post-entry, pre-reverse transcription step [#0, #1]. Recognition is achieved by direct binding of the C-terminal B30.2/PRY-SPRY domain to the assembled capsid lattice, mediated by hypervariable surface loops including the mobile v1 segment that bind CA assemblies in a manner paralleling antibody antigen recognition [#3, #8, #16]. Effective capsid capture requires higher-order self-assembly: TRIM5α dimers oligomerize through B-box 2 (dependent on a hydrophobic surface patch and Arg121) into a deformable hexagonal lattice whose spacing matches the underlying capsid, templated by the CA array [#11, #12, #26]. Engagement of the lattice promotes premature, accelerated capsid disassembly at inter-hexamer interfaces, rigidifying and allosterically destabilizing the CA shell and converting particulate capsid into soluble protein [#3, #14, #41]. TRIM5α is a RING-domain E3 ubiquitin ligase whose activity is potentiated by capsid-induced clustering: RING dimerization activates the K63-specific E2 Ubc13/Uev1A, with Ube2W initiating monoubiquitination and Ube2N/Ube2V2 elongating K63-linked chains, generating unanchored and N-terminally anchored polyubiquitin that activates TAK1-dependent AP-1 and NF-κB signaling and triggers proteasomal turnover of TRIM5α itself [#13, #15, #24, #25, #28]. Capsid encounter drives rapid proteasome-dependent degradation of TRIM5α, and although the proteasome executes core disruption, restriction can persist when it is inhibited, indicating TRIM5α acts at multiple steps [#5, #6, #10, #23]. Its activity is tuned by CypA, which shields HIV-1 from human TRIM5α restriction [#17, #29], by SUMOylation-dependent nuclear sequestration in dendritic cells that redirects TRIM5α toward cGAS-mediated IFN sensing [#37], by interferon induction and immunoproteasome reprogramming [#21, #30], and by dominant-negative spliced isoforms lacking the SPRY domain [#45]. In owl and pigtailed macaques, retrotransposition of CypA into the TRIM5 locus generated TRIMCyp fusions with CypA-dependent capsid recognition [#2, #22]. The same SPRY-based recognition extends restriction beyond retroviruses to tick-borne flavivirus NS2B/3 protease, orthopoxvirus L3 capsid protein, and LINE-1 retroelements [#38, #43, #39].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that a host factor blocks retroviruses after entry but before reverse transcription, defining TRIM5α as the species-specific capsid-acting restriction factor.\",\n      \"evidence\": \"siRNA knockdown and retroviral infectivity assays in Old World monkey cells; ortholog overexpression with capsid mutants\",\n      \"pmids\": [\"14985764\", \"15249690\", \"15249685\", \"15249687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of capsid recognition not yet defined\", \"Mechanism downstream of recognition unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that capsid recognition can be repurposed through a CypA fusion, establishing the modular nature of the recognition determinant via the natural TRIMCyp fusion.\",\n      \"evidence\": \"cDNA cloning, RNAi, functional transfer to human/rat cells, cyclosporin A inhibition in owl monkey cells\",\n      \"pmids\": [\"15243629\", \"15326303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether endogenous CypA modulates native TRIM5α\", \"Convergent independent fusions not yet known\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined TRIM5α oligomerization and identified that CypA acts upstream of TRIM5α, and that interferon transcriptionally induces TRIM5α.\",\n      \"evidence\": \"Analytical ultracentrifugation, co-IP, dominant-negative assays; dual RNAi epistasis; ISRE reporter and EMSA\",\n      \"pmids\": [\"16254380\", \"15919943\", \"16203999\", \"16289103\", \"16183097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligomeric state later revised to predominantly dimeric\", \"Mechanism of CypA shielding not resolved at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that direct B30.2-mediated capsid binding drives accelerated, premature uncoating, separating capsid disassembly from proteasome-dependent steps and showing restriction acts at multiple stages.\",\n      \"evidence\": \"Capsid binding and particulate/soluble CA assays, domain and capsid mutants, proteasome inhibitor with qPCR for RT products and in vitro integration\",\n      \"pmids\": [\"16540544\", \"17135314\", \"16973579\", \"16472833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the enzymatic basis of restriction\", \"Relationship between uncoating and signaling unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reconstituted TRIM5α E3 ubiquitin ligase activity and direct SPRY-mediated capsid binding with pure recombinant protein, proving the activities are intrinsic and require no other mammalian factors.\",\n      \"evidence\": \"Analytical ultracentrifugation, in vitro auto-ubiquitylation with multiple E2s, direct CA-NC binding via SPRY V1 loop; capsid-triggered degradation across restrictive pairs\",\n      \"pmids\": [\"18799573\", \"18312418\", \"18497858\", \"18287034\", \"18389077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain linkage type not yet defined\", \"Physiological E2 partner not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the B-box 2 structure and showed it drives higher-order self-association and avid capsid binding, identifying the assembly module underlying potent restriction.\",\n      \"evidence\": \"NMR structure of B-box 2, mutagenesis (cluster 1 patch, Arg121), capsid binding and infectivity assays\",\n      \"pmids\": [\"19656869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lattice geometry not directly visualized\", \"Link between assembly and enzymatic output unestablished\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Visualized TRIM5α self-assembly into hexagonal lattices templated by capsid arrays and showed direct in vitro capsid disruption, framing the deformable scaffold model of recognition.\",\n      \"evidence\": \"EM of 2D paracrystalline arrays with mutagenesis; EM of CA-NC disruption by lysate; coiled-coil specificity mutagenesis; live-cell imaging of cytoplasmic bodies; p62 dependency\",\n      \"pmids\": [\"21187419\", \"20410272\", \"20219908\", \"17392513\", \"20357094\", \"21035162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lattice assembly studied largely in vitro\", \"Cytoplasmic body function dissociated from restriction but role unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the K63-ubiquitin/TAK1 signaling axis and the structural basis of capsid disruption at inter-hexamer interfaces, unifying restriction and innate immune activation.\",\n      \"evidence\": \"In vitro K63 chain synthesis with UBC13-UEV1A, TAK1/UBC13 knockdown, NF-κB/AP-1 reporters; cryoEM and crosslinking of CA disruption; RING NMR structure with mutagenesis; SIM-dependent SUMO mechanism; isoform dominant negatives\",\n      \"pmids\": [\"21512573\", \"21455494\", \"21734049\", \"21490953\", \"21632761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of monoubiquitination versus chain elongation not resolved\", \"Substrate of K63 signaling versus auto-modification unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Determined the PRY/SPRY crystal structure, establishing that flexible hypervariable loops on a divergent face mediate capsid recognition akin to antibody antigen binding.\",\n      \"evidence\": \"X-ray crystallography of rhesus PRY/SPRY with biochemical CA binding and cryoEM\",\n      \"pmids\": [\"22847415\", \"23091002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity of monomeric versus assembled binding not quantified\", \"Determinants of species specificity at residue level incompletely mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the E2 enzyme cascade and the requirement of RING dimerization for K63 chain synthesis, linking capsid-induced higher-order assembly to enhanced E3 activity.\",\n      \"evidence\": \"In vitro ubiquitination reconstitution, E2 depletion, MS site mapping; crystal structure of RING:Ubc13-Ub with ultracentrifugation; AP-1/TAK1 ortholog panel\",\n      \"pmids\": [\"26101372\", \"26212332\", \"26468522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell stoichiometry of RING dimerization not directly measured\", \"Coupling of signaling to capsid disruption unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how B-box 2 trimers build the hexagonal net and sterically modulate RING dimerization, and revealed cell-type-specific routing of TRIM5α via Langerin in Langerhans cells.\",\n      \"evidence\": \"X-ray crystallography of B-box 2 with functional mutagenesis; siRNA, co-IP with Langerin/DC-SIGN, autophagy assays in primary DCs; CRISPR/siRNA showing autophagy dispensable for restriction\",\n      \"pmids\": [\"27253059\", \"27919079\", \"26764007\", \"26748714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagy contributes context-dependently remains conflicting (compare #31)\", \"Mechanism of Langerin-directed routing incompletely defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that lattice assembly triggers N-terminally anchored K63 chains that drive both signaling and degradation, with premature ubiquitination ablating restriction, establishing assembly-gated control of effector output.\",\n      \"evidence\": \"MS ubiquitin chain mapping, Ub mutant constructs, inducible ubiquitination, immune reporters; MAS-NMR showing capsid rigidification by TRIM5α\",\n      \"pmids\": [\"30503508\", \"30333189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo readers of N-K63-Ub not identified\", \"Quantitative link between rigidification and disassembly unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the long-standing question of human TRIM5α potency by showing CypA shields HIV-1 and that immunoproteasome reprogramming converts human TRIM5α into a potent restrictor.\",\n      \"evidence\": \"CRISPR/siRNA in primary cells, CA-CypA mutant viruses, core co-fractionation; IFN-α siRNA screen with immunoproteasome subunit depletion; flavivirus NS2B/3 targeting by co-IP and ubiquitination\",\n      \"pmids\": [\"31636416\", \"30886358\", \"31189110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How immunoproteasome turnover mechanistically switches activity not fully defined\", \"Breadth of flavivirus substrate specificity limited to tick-borne complex\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended TRIM5α function to LINE-1 retroelement sensing and refined the lattice model with simulation, mapping the CA binding interface near the CypA loop.\",\n      \"evidence\": \"Co-IP with LINE-1 RNPs, retrotransposition and immune reporters; coarse-grained MD validated by cryoET\",\n      \"pmids\": [\"32651277\", \"32161265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LINE-1 RNP recognition determinant not structurally defined\", \"Binding interface localization by simulation lacks direct mutagenesis\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that pandemic HIV-1 evolved specific capsid adaptations that evade TRIM5 triggering, showing the host-pathogen arms race at the structural level.\",\n      \"evidence\": \"Phylogenetics, X-ray crystallography of capsid variants, reversal genetics in myeloid cells with immune reporters\",\n      \"pmids\": [\"36289397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other lentiviral lineages use the same evasion strategy unknown\", \"Structural basis of evasion at the TRIM5 interface incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established TRIM5α as a poxvirus restriction factor with a dedicated viral antagonist, broadening its antiviral scope beyond retroelements and RNA viruses.\",\n      \"evidence\": \"Co-IP with orthopoxvirus L3 and vaccinia C6, proteasome rescue, TRIM5α knockout infectivity, CsA and cyclosporine derivative assays\",\n      \"pmids\": [\"37558876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether L3 forms a lattice-like ligand is unknown\", \"Generality of poxvirus restriction across orthopoxvirus species untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM5α-generated polyubiquitin signals are decoded by downstream effectors in vivo, and how a single SPRY-based recognition module is tuned to such diverse ligands (retroviral lattices, flavivirus protease, poxvirus capsid, LINE-1 RNPs), remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain readers downstream of TRIM5α not identified\", \"Unifying determinants of broad SPRY ligand specificity unresolved\", \"Physiological contribution of nuclear/IFN-sensing versus cytoplasmic restriction in vivo unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [8, 9, 13, 15, 24, 25, 28]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [13, 24, 38]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 33, 36, 39]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 3, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11, 12, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 36, 37, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 38, 43]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 33, 36]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [24, 28, 38, 43]}\n    ],\n    \"complexes\": [\n      \"TRIM5\\u03b1 hexagonal capsid-templated lattice\"\n    ],\n    \"partners\": [\n      \"CypA\",\n      \"Ube2N/UBC13\",\n      \"Ube2V2/UEV1A\",\n      \"Ube2W\",\n      \"TAK1\",\n      \"Langerin\",\n      \"p62/SQSTM1\",\n      \"TAB2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}