{"gene":"TRIM22","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"TRIM22 inhibits HIV-1 particle release by targeting HIV Gag, disrupting its trafficking to the plasma membrane; the RING domain catalytic residues Cys15 and Cys18 are required for this antiviral activity. TRIM22 does not block MLV or EIAV Gag particle release, indicating specificity for HIV Gag.","method":"RNAi knockdown, overexpression, virus-like particle budding assay, mutational analysis of RING domain (C15A/C18A), fluorescence microscopy of Gag localization","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, OE, mutagenesis, imaging), independently replicated concept across multiple labs","pmids":["18389079"],"is_preprint":false},{"year":2008,"finding":"TRIM22 is a functional E3 ubiquitin ligase that catalyzes self-ubiquitylation in vitro in combination with E2 enzyme UbcH5B, dependent on its RING finger domain; TRIM22 also undergoes self-ubiquitylation in vivo and is targeted for proteasomal degradation via poly-ubiquitin chains. TRIM22 localizes to the nucleus.","method":"In vitro ubiquitylation assay with UbcH5B, in vivo ubiquitylation in 293T cells, proteasome inhibitor stabilization assay, subcellular fractionation/localization","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of E3 activity with E2, in vivo confirmation, single lab with multiple orthogonal methods","pmids":["18656448"],"is_preprint":false},{"year":2009,"finding":"TRIM22 E3 ubiquitin ligase activity is required for antiviral protection against encephalomyocarditis virus (ECMV); TRIM22 interacts with the viral 3C protease (3C^PRO) and mediates its ubiquitination. A RING domain deletion mutant abolishes both E3 activity and antiviral effect.","method":"Antiviral protection assay in HeLa cells, co-immunoprecipitation of TRIM22 with 3C^PRO, ubiquitination assay, RING deletion mutant analysis","journal":"The Journal of general virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and domain mutant with functional readout in single lab, multiple orthogonal methods","pmids":["19218198"],"is_preprint":false},{"year":2011,"finding":"TRIM22 inhibits HIV-1 LTR-driven transcription independently of its E3 ubiquitin ligase activity, Tat transactivation, and NF-κB binding sites in the LTR. Nuclear TRIM22 suppresses basal and phorbol ester-induced HIV-1 transcription.","method":"Stable TRIM22 knockdown in U937 cells, TRIM22 transduction in permissive cells, LTR-luciferase reporter assays with NF-κB site deletion constructs, RING mutant (E3-dead) analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell systems, reporter assays with deletion constructs, E3-dead mutant, replicated concept in subsequent studies","pmids":["21345949"],"is_preprint":false},{"year":2013,"finding":"TRIM22 restricts influenza A virus (IAV) replication by interacting with the viral nucleoprotein (NP) and promoting its polyubiquitination and proteasome-dependent degradation.","method":"shRNA knockdown, overexpression in MDCK cells, Co-IP of TRIM22 with NP, ubiquitination assay, proteasome inhibitor rescue, viral titer measurement","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome inhibitor rescue, KD and OE with functional readout, single lab multiple orthogonal methods","pmids":["23408607"],"is_preprint":false},{"year":2011,"finding":"TRIM22 activates NF-κB in a dose-dependent manner; both the N-terminal RING domain and C-terminal SPRY domain are required for NF-κB activation. TRIM22 overexpression induces pro-inflammatory cytokine secretion in U937 macrophages in an NF-κB-dependent manner.","method":"NF-κB luciferase reporter assay, EMSA, domain deletion mutants, cytokine ELISA","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter assay and EMSA with domain mutants, single lab, single study","pmids":["21651891"],"is_preprint":false},{"year":2015,"finding":"TRIM22 inhibits HIV-1 LTR-driven transcription by preventing Sp1 binding to the viral promoter; TRIM22 does not interact directly with Sp1 but blocks Sp1 binding as shown by protein-DNA pulldown and chromatin immunoprecipitation.","method":"Reporter assays with Sp1-binding-site deletion constructs in 293T cells, TRIM22 KD in SupT1 T cells with HIV replication assay, protein-DNA pulldown, chromatin immunoprecipitation (ChIP)","journal":"Retrovirology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP and protein-DNA pulldown showing TRIM22 blocks Sp1 binding, reporter assays, KD phenotype, multiple orthogonal methods","pmids":["26683615"],"is_preprint":false},{"year":2015,"finding":"TRIM22 ubiquitinates HCV NS5A protein in a concentration-dependent manner, and TRIM22 expression inhibits HCV replication; siRNA-mediated TRIM22 knockdown diminishes IFNα-induced anti-HCV function.","method":"TRIM22 overexpression and siRNA knockdown in Huh-7 cells, HCV replication assay, NS5A ubiquitination assay","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination assay and KD/OE with functional readout, single lab","pmids":["25683609"],"is_preprint":false},{"year":2013,"finding":"TRIM22 inhibits the TRAF6-stimulated NF-κB pathway by interacting with and degrading TAB2 in a RING domain-dependent manner; TRIM22 also decreases TRAF6 self-ubiquitination.","method":"NF-κB reporter assay, Co-IP of TRIM22 with TAB2, TAB2 degradation assay with RING deletion mutant, TRAF6 ubiquitination assay","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and degradation assay with domain mutant, single lab","pmids":["23818111"],"is_preprint":false},{"year":2004,"finding":"TRIM22 (Staf50) is a direct p53 target gene; a functional p53-response element in intron 1 mediates direct p53 binding (shown by EMSA) and transactivation; p53-family member p73 also transactivates via this element. Ectopic TRIM22 expression reduces clonogenic growth of U937 leukemic cells.","method":"cDNA microarray, cycloheximide chase (independence of de novo protein synthesis), EMSA, luciferase reporter assay with intron 1 p53-RE, ectopic expression clonogenic assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — EMSA showing direct p53 binding, reporter assay, functional growth assay, multiple orthogonal methods","pmids":["15064739"],"is_preprint":false},{"year":2009,"finding":"Human and rhesus TRIM22 localize to different subcellular compartments, and this difference maps to the B30.2/SPRY domain; amino acid changes in variable loops VL1 and VL3 of the B30.2 domain are responsible for the species-specific subcellular localization differences.","method":"Fluorescence microscopy of GFP-tagged constructs, domain swap/chimeric protein experiments, mutational analysis of VL1 and VL3","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by imaging with domain mutants, single lab","pmids":["19212762"],"is_preprint":false},{"year":2009,"finding":"Endogenous TRIM22 colocalizes with centrosomes independently of cell cycle phase in primary human mononuclear cells and U2OS cells, and this colocalization is independent of the microtubule network.","method":"Immunofluorescence of endogenous TRIM22 with centrosome markers, microtubule depolymerization experiment, cell cycle staging","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — direct localization imaging, single lab, no functional consequence demonstrated","pmids":["20006605"],"is_preprint":false},{"year":2012,"finding":"TRIM22 directly or indirectly interacts with translation initiation factor eIF4E and inhibits eIF4E binding to eIF4G, thereby disrupting eIF4F complex assembly and repressing cap-dependent translation of specific mRNAs including IRF-7C.","method":"Co-immunoprecipitation of TRIM22 with eIF4E, eIF4G binding competition assay, luciferase reporter assay, radiolabelled methionine incorporation assay","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP, functional translation assay, single lab","pmids":["22509910"],"is_preprint":false},{"year":2015,"finding":"TRIM22 activates the noncanonical NF-κB pathway by interacting with IKKα (but not IKKβ) via its RING and SPRY domains, increasing IKKα levels and phosphorylation, and inducing p100 processing to p52.","method":"Co-immunoprecipitation, co-localization, Western blot for p100/p52 processing and IKKα phosphorylation, domain deletion mutants","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and co-localization with domain mutants, single lab","pmids":["25510414"],"is_preprint":false},{"year":2016,"finding":"TRIM22 variants disrupt the ability of TRIM22 to regulate NOD2-dependent activation of IFN-β signaling and NF-κB, establishing TRIM22 as a regulator of the NOD2 signaling pathway in a disease context (very-early-onset IBD).","method":"Whole-exome sequencing, functional studies in primary patient cells and cell culture showing disrupted NOD2/IFN-β/NF-κB signaling by TRIM22 variants","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional cell studies with patient-derived variants, single lab report","pmids":["26836588"],"is_preprint":false},{"year":2020,"finding":"TRIM22 promotes NF-κB signaling in GBM by: (1) binding IκBα and accelerating its degradation via K48-linked ubiquitination; (2) forming a complex with IKKγ and promoting K63-linked ubiquitination leading to IKKα/β and IκBα phosphorylation. RING domain E3 ligase activity is required for these effects. A non-phosphorylatable IκBα mutant (srIκBα) blocks TRIM22 growth-promoting activity.","method":"Co-immunoprecipitation, K48/K63-linked ubiquitination assays, Cas9-sgRNA knockout, RING mutant (C15/18A) and deletion analysis, NF-κB luciferase reporter, orthotopic xenograft model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, linkage-specific ubiquitination assays, RING mutant, in vivo xenograft, multiple orthogonal methods","pmids":["32814880"],"is_preprint":false},{"year":2022,"finding":"TRIM22 promotes proteasomal degradation of NRF2 via E3 ligase-dependent ubiquitination that is independent of KEAP1, reducing intracellular antioxidant capacity and activating ROS/AMPK/mTOR/autophagy signaling to induce autophagic cell death in osteosarcoma.","method":"Co-immunoprecipitation of TRIM22 with NRF2, ubiquitination assay, E3 ligase mutant analysis, ROS measurement, AMPK/mTOR pathway Western blot, in vitro and in vivo gain/loss-of-function with rescue by NRF2 manipulation or NAC/3-MA","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, E3 mutant, rescue experiments, in vivo xenograft, multiple orthogonal methods","pmids":["35636015"],"is_preprint":false},{"year":2022,"finding":"TRIM22 suppresses Zika virus (ZIKV) replication by interacting with viral NS1 and NS3 proteins and promoting their ubiquitination and proteasomal degradation; the SPRY domain mediates protein interaction and the RING domain mediates degradation. TRIM22 also inhibits dengue and yellow fever virus.","method":"Co-immunoprecipitation, ubiquitination assay, domain deletion analysis (SPRY and RING), overexpression and TRIM22 KO cell infectivity assay, proteasome inhibitor rescue","journal":"Cell & bioscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, domain-specific mutants, ubiquitination assay, KO functional assay, single lab multiple orthogonal methods","pmids":["36042495"],"is_preprint":false},{"year":2024,"finding":"TRIM22 E3 ubiquitin ligase promotes proteasomal degradation of SARS-CoV-2 NSP8 via K48-type ubiquitination at Lys97, thereby restricting viral replication; TRIM22 expression is induced by interferon signaling upon SARS-CoV-2 infection.","method":"Co-immunoprecipitation of TRIM22 with NSP8, K48-ubiquitination assay with site-specific Lys97 mutation, TRIM22 overexpression and knockdown viral replication assay","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination mutant (K97), KD and OE with viral readout, single lab multiple orthogonal methods","pmids":["38275298"],"is_preprint":false},{"year":2023,"finding":"TRIM22 induces cellular senescence in hepatocellular carcinoma by targeting PHLPP2 for proteasomal degradation via the SPRY domain binding PHLPP2's C-terminal IKKβ-phosphorylated domain; PHLPP2 degradation activates AKT-p53-p21 signaling leading to senescence.","method":"Co-immunoprecipitation with domain mapping, ubiquitination assay, IKKβ phosphorylation analysis, AKT/p53/p21 Western blot, cellular senescence assays (β-galactosidase, SAHF), p53 ChIP for TRIM22 promoter","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-specific Co-IP, ubiquitination, phosphorylation-dependent mechanism, multiple orthogonal methods, single lab","pmids":["38199981"],"is_preprint":false},{"year":2023,"finding":"TRIM22 promotes GBM proliferation by activating MAPK signaling; it binds Raf-1 (a negative regulator) via CC and SPRY domains and accelerates Raf-1 degradation by K48-linked ubiquitination (interaction requires Raf-1 C1D domain). TRIM22 also binds the SPHK2 gene at exon 2 to regulate SPHK2 transcription.","method":"Co-immunoprecipitation with domain mapping, K48-ubiquitination assay, ERK1/2 luciferase reporter, TRIM22 KO and OE, RING domain and NLS deletion mutants, in vivo xenograft","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with domain mutants, ubiquitination assay, single lab","pmids":["37258577"],"is_preprint":false},{"year":2015,"finding":"TRIM22 ubiquitinates FoxO4 and targets it for degradation via the autophagosomal-lysosomal (not ubiquitin-proteasome) pathway; this antagonizes FoxO4's role in promoting IFN-β expression downstream of TLR3/RIG-I activation. TRIM22 knockdown sensitizes cells to dsRNA-induced caspase-dependent apoptosis and suppresses Bcl-2.","method":"TRIM22 KD with poly(I:C) stimulation, FoxO4 KD, IFN-β reporter assay, assessment of FoxO4 protein levels, apoptosis assay (caspase activation), Bcl-2 Western blot","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — indirect evidence for lysosomal degradation pathway, reporter and apoptosis assay, single lab","pmids":["26237181"],"is_preprint":false},{"year":2017,"finding":"HBV X protein (HBx) suppresses TRIM22 transcription through a single CpG methylation in the TRIM22 5'-UTR, which reduces IRF-1 binding affinity to the TRIM22 promoter, thereby enabling HBV to evade innate immune restriction.","method":"LC-MS/MS proteomics, bisulfite sequencing for CpG methylation, IRF-1 binding assay, mouse model, primary human hepatocytes","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Moderate — methylation mapped to single CpG, IRF-1 binding assay, validated in mouse model and primary cells, multiple orthogonal methods","pmids":["28341749"],"is_preprint":false},{"year":2011,"finding":"BRG1 (chromatin remodeling ATPase) is required for IFN-γ-induced TRIM22 expression; BRG1 deficiency does not impair IFN-γ-induced IRF-1 expression but blocks IRF-1 access to the TRIM22 promoter; BRG1 ATPase domain is required for TRIM22 induction and IRF-1 recruitment.","method":"BRG1-deficient SW-13 cell line with BRG1 reconstitution, ChIP of IRF-1 at TRIM22 promoter, BRG1 ATPase domain mutant","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP with domain mutant, single lab, isogenic cell line system","pmids":["21683060"],"is_preprint":false},{"year":2013,"finding":"p300, but not PCAF, functions as a transcriptional co-activator of IRF-1 for IFN-γ-induced TRIM22 expression independently of p300's histone acetyltransferase activity; p300 is required for RNA polymerase II recruitment to the TRIM22 promoter.","method":"In vitro DNA affinity binding assay, ChIP of p300 and RNA Pol II at TRIM22 promoter, p300 overexpression and knockdown, HAT-dead p300 mutant","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP, in vitro binding, HAT-dead mutant, single lab","pmids":["23670564"],"is_preprint":false},{"year":2015,"finding":"TRIM22 is a progesterone-receptor (PR) direct target gene; PR binds a progesterone response element (PRE) in the TRIM22 promoter region (-25 to -11 bp upstream of exon 1) in a hormone-dependent manner, and this PRE has enhancer activity.","method":"ChIP of PR at TRIM22 PRE, luciferase reporter assay for PRE activity, PR-stable Ishikawa cell clones, hormone-dependent TRIM22 expression","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and reporter assay for direct transcriptional regulation, single lab","pmids":["26316153"],"is_preprint":false},{"year":2019,"finding":"TRIM22 maintains HIV-1 proviral latency in T cell lines; TRIM22 knockdown accelerates reactivation of a dox-controlled HIV-1 in SupT1 cells and potentiates HIV-1 expression in ACH-2 and J-Lat 10.6 cell lines upon TNF-α or HDAC inhibitor stimulation.","method":"TRIM22 knockdown in T cell lines, dox-controlled HIV-1 replication system, TNF-α/HDACi stimulation, HIV-1 p24 and luciferase readouts","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined functional readout in multiple T cell lines, single lab","pmids":["31136823"],"is_preprint":false},{"year":2019,"finding":"TRIM22 interacts with PRRSV nucleocapsid (N) protein through its SPRY domain; the NLS2 motif of N protein is involved in the interaction with TRIM22. The NLS (nuclear localization signal) and SPRY domain of TRIM22 are both required for inhibition of PRRSV replication; however, PRRSV N protein levels are not altered by TRIM22, whereas N proteins from related arteriviruses (SHFV, EAV, LDV) are reduced by TRIM22 overexpression.","method":"Co-IP, TRIM22 domain deletion constructs (ΔSPRY, ΔNLS), ectopic expression and RNAi in MARC-145 cells, viral titer measurement","journal":"Virus genes","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP with domain mapping, single lab","pmids":["31375995"],"is_preprint":false},{"year":2021,"finding":"TRIM22 restricts HSV-1 replication by increasing histone occupancy and heterochromatin on viral immediate-early gene promoters, thereby reducing viral IE gene expression; this represents an epigenetic restriction mechanism independent of ICP0-mediated degradation.","method":"TRIM22 KO and overexpression, ChIP for histone occupancy and heterochromatin marks at viral IE promoters, ICP0-null and wild-type virus comparison, viral gene expression analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP with KO/OE, ICP0-null vs WT comparison, mechanistic epigenetic readout, single lab multiple orthogonal methods","pmids":["33524065"],"is_preprint":false},{"year":2023,"finding":"TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, independently of its E3 ubiquitin ligase activity; a TRIM22 variant associated with familial Alzheimer disease interferes with this function and impairs autophagic clearance.","method":"Co-IP, proximity ligation assay, TRIM22 KO with autophagy flux assay, E3 ligase-dead mutant analysis, Alzheimer variant functional testing in cells","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, PLA, KO with functional autophagy readout, E3-dead mutant, multiple orthogonal methods, single lab","pmids":["38009729"],"is_preprint":false},{"year":2021,"finding":"TRIM22 promotes PRRSV N protein degradation through the lysosomal pathway by interacting with LC3; PRRSV miR-376b-3p directly targets TRIM22 to impair its anti-PRRSV activity.","method":"Co-IP of TRIM22 with PRRSV N protein and LC3, lysosomal pathway inhibitor experiments, miRNA target validation, viral replication assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP with lysosomal pathway inhibitors, single lab","pmids":["34757838"],"is_preprint":false},{"year":2017,"finding":"TRIM22 mediates apoptosis in monocytes by promoting Bak expression and oligomerization; both the RING and SPRY domains are required. TRIM22 overexpression activates caspase-9 and caspase-3.","method":"TRIM22 overexpression in THP-1 and primary monocytes, domain deletion mutants (ΔRING, ΔSPRY), caspase activation assay, Bak oligomerization analysis by native PAGE/fractionation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — domain mutants with functional apoptosis readout, single lab","pmids":["28079123"],"is_preprint":false},{"year":2022,"finding":"TRIM22 forms a complex with NT5C2 in GBM and differentially regulates RIG-I ubiquitination: TRIM22 promotes K63-linked ubiquitination of RIG-I while NT5C2 promotes K48-linked ubiquitination, regulating the RIG-I/NF-κB/CCAR1 signaling axis.","method":"Co-IP, K48/K63-specific ubiquitination assays, TRIM22 KO with RIG-I ubiquitination readout, luciferase reporter, in vivo xenograft","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, linkage-specific ubiquitination assays, single lab","pmids":["36159777"],"is_preprint":false},{"year":2024,"finding":"TRIM22 interacts with PHLPP2 (AKT phosphatase) and induces its proteasomal degradation, leading to AKT activation and cellular senescence via AKT-p53-p21 signaling; IKKβ-mediated phosphorylation of PHLPP2's C-terminal domain is a prerequisite for TRIM22-SPRY-domain-mediated recognition.","method":"Co-IP with SPRY domain mapping, ubiquitination assay, IKKβ phosphorylation analysis, AKT/p53/p21 Western blot, β-galactosidase and SAHF senescence assays, TRIM22 KO/OE","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-specific Co-IP, phospho-dependent ubiquitination, multiple orthogonal functional assays, single lab","pmids":["38199981"],"is_preprint":false},{"year":2024,"finding":"TRIM22 ubiquitinates copper chaperone CCS via K27-linked ubiquitination at CCS Lys76, requiring the TRIM22 coiled-coil domain; CCS degradation suppresses STAT3 phosphorylation by increasing ROS, inhibiting breast cancer proliferation and invasion.","method":"Label-free proteomics, Co-IP, ubiquitination assay with linkage-specific antibodies, site-directed mutagenesis (K76R of CCS), TRIM22 coiled-coil domain deletion mutant, ChIP-qPCR, ROS measurement, RNA-seq GSEA","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-specific Co-IP, site-specific ubiquitination mutant, multiple orthogonal methods, single lab","pmids":["39127340"],"is_preprint":false},{"year":2024,"finding":"WTAP promotes m6A modification of TRIM22 5'UTR via the m6A reader IGF2BP1, increasing TRIM22 expression; TRIM22 then interacts with OPA1 and induces its ubiquitination, causing mitochondrial dysfunction in diabetic nephropathy.","method":"RNA immunoprecipitation for m6A detection of TRIM22 5'UTR, Co-IP of TRIM22 with OPA1, ubiquitination assay, mitochondrial function assays","journal":"Redox report","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and RIP assay, single lab","pmids":["39314036"],"is_preprint":false},{"year":2025,"finding":"TRIM22 enhances RIG-I-mediated antiviral signaling by catalyzing K63-linked polyubiquitination of MAVS, activating the TBK1/IRF3 pathway and IFN-β production; TRIM22 also inhibits the MAVS-NLRX1 inhibitory complex assembly. RNA virus infection induces TRIM22 expression via nuclear translocation of transcription factor ELF3, which activates TRIM22 gene transcription.","method":"Co-IP, K63-specific ubiquitination assay of MAVS, TRIM22 KO/KD with IFN-β reporter and TBK1/IRF3 phosphorylation assay, ELF3 nuclear translocation and ChIP/reporter assay for TRIM22 promoter, MAVS-NLRX1 Co-IP","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — K63-ubiquitination assay, KO functional readout, promoter ChIP, multiple pathways assessed, multiple orthogonal methods","pmids":["40162781"],"is_preprint":false},{"year":2025,"finding":"TRIM22 functions as a scaffold protein for autophagy initiation: SPRY domain mediates interaction with ATG13 and FIP200; N-terminal region interacts with ULK1 and ATG101; B-box domain is required for interaction with Beclin-1 and assembly of the class III PI3K complex; Beclin-1 and PLEKHM1 compete for overlapping TRIM22 binding regions. This function is independent of E3 ubiquitin ligase activity.","method":"Co-IP with domain deletion constructs, competitive binding assay, autophagy flux assay (LC3-II, autophagic clearance), TRIM22 KO, mTOR/AMPK activity measurement, primary neuron experiments","journal":"Animal cells and systems","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-specific Co-IP, competitive binding, E3-dead mutant, KO with autophagic flux readout, multiple orthogonal methods","pmids":["40337095"],"is_preprint":false},{"year":2024,"finding":"TRIM22 ubiquitinates TCF4 via K48-linked ubiquitination mediated by the TRIM22 RING domain, leading to TCF4 proteasomal degradation and suppression of ovarian cancer cell proliferation and invasion.","method":"Co-IP, ubiquitination assay with RING domain deletion mutant, rescue of TRIM22 phenotype by TCF4 overexpression","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination with domain mutant, single lab","pmids":["38842601"],"is_preprint":false},{"year":2025,"finding":"TRIM22 promotes K63-linked ubiquitination of p21 via its SPRY domain (interaction) and RING domain (catalysis), inducing p21 degradation through the proteasome pathway to accelerate cell cycle progression in melanoma.","method":"S-protein pulldown of p21 with TRIM22 SPRY domain, ubiquitination assay (K63-linked), CHX chase confirming proteasomal degradation, p21 KD epistasis experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pulldown, K63-ubiquitination assay, epistasis experiment, single lab","pmids":["40593126"],"is_preprint":false},{"year":2025,"finding":"TRIM22 ubiquitinates and degrades CDT2 (CRL4 subunit), acting as a novel E3 ligase for CDT2 in HPV-positive cervical cancer cells; E6-mediated p53 degradation downregulates TRIM22 (a p53 target), leading to CDT2 accumulation that promotes cancer cell growth and survival.","method":"Ubiquitination assay of CDT2 by TRIM22, Western blot and KD/OE for CDT2/TRIM22 relationship, epistasis with E6/E7, p53 transcription of TRIM22","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — ubiquitination assay and KD, single lab","pmids":["40680432"],"is_preprint":false},{"year":2025,"finding":"TRIM22 interacts with KAT2A and promotes its ubiquitination-dependent degradation in melanoma cells; loss of TRIM22 allows KAT2A accumulation, which binds the Notch1 promoter to increase H3K9ac and activate Notch1 transcription, promoting cancer stemness.","method":"Co-IP, ubiquitination assay, ChIP of KAT2A at Notch1 promoter for H3K9ac, TRIM22 KO/OE, Notch1 inhibitor rescue","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP, ChIP with KO/OE, single lab","pmids":["37415153"],"is_preprint":false},{"year":2025,"finding":"HOXC8 transcriptionally activates TRIM22 expression; TRIM22 then ubiquitinates and degrades IκBα, activating NF-κB signaling to drive stemness maintenance in colorectal cancer cells.","method":"Luciferase reporter and ChIP for HOXC8-TRIM22 promoter interaction, ubiquitination assay of IκBα by TRIM22, NF-κB activity and stemness markers","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — reporter, ChIP, and ubiquitination assay, single lab","pmids":["41265630"],"is_preprint":false},{"year":2025,"finding":"TRIM22 interacts with ADRB2 (β-2 adrenergic receptor) and negatively regulates ADRB2 expression and JAK2/STAT3 signaling in lung adenocarcinoma cells.","method":"STRING database prediction, co-immunoprecipitation of TRIM22 with ADRB2, ADRB2 and TRIM22 KD/OE with JAK2/STAT3 Western blot and cell proliferation assay","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP without mechanistic ubiquitination analysis, single lab","pmids":["40594822"],"is_preprint":false},{"year":2021,"finding":"Constitutive TRIM22 expression in lung/respiratory tract epithelia (independent of IFN stimulation) is sufficient to restrict influenza A virus replication by inhibiting viral transcription onset, representing an intrinsic (pre-existing) defense.","method":"Transcriptomic analysis of human tissues, primary respiratory cell lines, rhesus macaque airway TRIM22 expression, TRIM22 KD with IAV replication assay (viral transcript measurement), comparison of IFN-dependent vs constitutive expression","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with viral transcription readout in primary cells and in vivo tissues, single lab","pmids":["34621686"],"is_preprint":false},{"year":2022,"finding":"TRIM22 negatively regulates MHC class II protein expression through a mechanism other than transcription or protein degradation; TRIM22 KO increases MHC-II protein levels while OE decreases them, without affecting CIITA or MHC-II mRNA levels.","method":"Cas9-sgRNA knockout and TRIM22 overexpression, Western blot for MHC-II protein and mRNA (qPCR), cycloheximide chase for MHC-II degradation","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KO/OE with protein level readout, mechanism not fully elucidated, single lab","pmids":["35777501"],"is_preprint":false},{"year":2025,"finding":"TRIM22 promotes GBM cell survival by stabilizing Bcl-2 via non-degradative (non-K48) ubiquitination; TRIM22 binds Bcl-2 and increases its protein expression levels.","method":"Immunoprecipitation of TRIM22-Bcl-2 complex, ubiquitination microarray, ubiquitination assay, Western blot, flow cytometry apoptosis assay","journal":"Molecular & cellular oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab","pmids":["40552115"],"is_preprint":false},{"year":2024,"finding":"TRIM22 directly interacts with KAT2A and promotes KAT2A ubiquitination and degradation in hepatocellular carcinoma cells, reducing H3K9ac enrichment at the GPX4 promoter and promoting ferroptosis through the KAT2A/GPX4 axis; O-GlcNAcylation of KAT2A at S583 blocks TRIM22-mediated ubiquitination, stabilizing KAT2A.","method":"Co-IP of TRIM22 with KAT2A, ubiquitination assay, ChIP-qPCR for H3K9ac at GPX4 promoter, ferroptosis markers (Fe2+, MDA, ROS, GSH), O-GlcNAcylation site mutant (S583A), in vivo tumor model","journal":"Histology and histopathology / Cancer science","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP, ChIP, ubiquitination, single lab each study","pmids":["39698827","42114931"],"is_preprint":false},{"year":2025,"finding":"TRIM22 inhibits colorectal cancer metastasis by directly interacting with and ubiquitinating β-Catenin, promoting its degradation and inhibiting EMT; this anti-metastatic effect depends on TRIM22 E3 ligase activity.","method":"Co-IP of TRIM22 with β-Catenin, ubiquitination assay, TRIM22 OE/KD with β-Catenin rescue, in vivo metastasis model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination with rescue, single lab","pmids":["39978715"],"is_preprint":false},{"year":2022,"finding":"TRIM22 negatively regulates TLR3-induced CCL5 expression in human renal proximal tubular epithelial cells; TRIM22 is induced downstream of IFN-β in a TLR3-IFN-β-TRIM22 pathway, and its knockdown upregulates poly(I:C)-induced CCL5 production.","method":"siRNA knockdown of TRIM22 and IFN-β, poly(I:C) stimulation, TRIM22/CCL5/IFN-β mRNA and protein quantification in hRPTECs","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — KD with defined pathway and functional readout, single lab","pmids":["40080304"],"is_preprint":false},{"year":2022,"finding":"TRIM22 directly interacts with Smad2 in gastric cancer cells; overexpression of TRIM22 downregulates Smad2 phosphorylation and Smad3 phosphorylation; Smad2 overexpression reverses TRIM22-induced inhibition of proliferation and migration.","method":"Co-IP of TRIM22 with Smad2, Western blot for p-Smad2/3, rescue experiment with Smad2 overexpression, in vivo xenograft","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP with epistasis rescue, single lab","pmids":["34489426"],"is_preprint":false}],"current_model":"TRIM22 is an interferon-inducible, p53-regulated RING-type E3 ubiquitin ligase that restricts diverse viruses (HIV-1, IAV, ECMV, HCV, ZIKV, SARS-CoV-2, HSV-1) through multiple mechanisms: direct ubiquitination and proteasomal degradation of viral proteins (HIV Gag trafficking disruption, IAV NP, ECMV 3C^PRO, HCV NS5A, ZIKV NS1/NS3, SARS-CoV-2 NSP8); epigenetic silencing of the HIV-1 LTR by blocking Sp1 binding (E3-independent); K63-linked polyubiquitination of MAVS to amplify TBK1/IRF3/IFN-β signaling; and epigenetic deposition of heterochromatin on HSV-1 IE gene promoters. In cancer and non-viral settings, TRIM22 ubiquitinates numerous substrates (NRF2, IκBα, PHLPP2, Raf-1, TAB2, CCS, KAT2A, p21, β-Catenin, CDT2, OPA1, Bcl-2) to modulate NF-κB, MAPK, AKT, and autophagy signaling, and also acts as an E3-independent scaffold that promotes autophagosome–lysosome fusion (via GABARAP-PLEKHM1 bridging) and autophagy initiation (via ULK1/ATG13/FIP200/Beclin-1 complex assembly through distinct TRIM22 domains)."},"narrative":{"mechanistic_narrative":"TRIM22 is an interferon- and p53-inducible RING-type E3 ubiquitin ligase that acts as a broad antiviral restriction factor and, in non-viral settings, as a regulator of NF-κB, MAPK/AKT, and autophagy signaling [PMID:15064739, PMID:18656448, PMID:32814880]. As an E3 ligase it self-ubiquitylates in vitro with the E2 UbcH5B through its RING domain and is itself degraded by the proteasome [PMID:18656448]. Against viruses it engages diverse viral proteins—typically via its C-terminal SPRY/B30.2 domain—and targets them for RING-dependent ubiquitination and proteasomal degradation, including influenza A NP [PMID:23408607], Zika NS1/NS3 [PMID:36042495], and SARS-CoV-2 NSP8 (K48-linked at Lys97) [PMID:38275298], while disrupting trafficking of HIV-1 Gag [PMID:18389079] and ubiquitinating the picornaviral 3C protease and HCV NS5A [PMID:19218198, PMID:25683609]. TRIM22 also restricts viruses through ligase-independent mechanisms: it silences the HIV-1 LTR by blocking Sp1 occupancy of the promoter [PMID:21345949, PMID:26683615], maintains HIV-1 proviral latency [PMID:31136823], and deposits heterochromatin on HSV-1 immediate-early promoters [PMID:33524065]. It additionally amplifies innate signaling by catalyzing K63-linked polyubiquitination of MAVS to drive TBK1/IRF3/IFN-β output [PMID:40162781]. In cancer and other non-viral contexts TRIM22 ubiquitinates numerous substrates—NRF2, IκBα, PHLPP2, Raf-1, CCS, β-Catenin—to modulate antioxidant, NF-κB, MAPK, AKT-p53-p21, and senescence programs [PMID:35636015, PMID:32814880, PMID:38199981, PMID:37258577, PMID:39127340, PMID:39978715]. Beyond its catalytic activity, TRIM22 serves as an E3-independent scaffold that promotes autophagosome–lysosome fusion by bridging GABARAP-family proteins to PLEKHM1 and nucleates autophagy initiation by assembling ULK1/ATG13/FIP200 and Beclin-1 PI3K complexes through distinct domains [PMID:38009729, PMID:40337095]. TRIM22 variants are linked to very-early-onset inflammatory bowel disease through disrupted NOD2-dependent signaling [PMID:26836588] and to a familial Alzheimer disease phenotype through impaired autophagic clearance [PMID:38009729]. Its own expression is controlled at the promoter by IRF-1 (with BRG1 and p300), p53, progesterone receptor, HOXC8, and ELF3, and is suppressed by HBV via 5'-UTR CpG methylation [PMID:21683060, PMID:23670564, PMID:15064739, PMID:26316153, PMID:41265630, PMID:40162781, PMID:28341749].","teleology":[{"year":2004,"claim":"Established TRIM22 as a directly transcriptionally regulated effector, placing it downstream of the p53 tumor-suppressor network and connecting it to growth control.","evidence":"cDNA microarray, EMSA, and reporter assays identifying a functional p53-response element in intron 1, with a clonogenic growth assay in leukemic cells","pmids":["15064739"],"confidence":"High","gaps":["Did not define the ubiquitin-ligase substrates mediating growth suppression","p73 contribution to physiological regulation unresolved"]},{"year":2008,"claim":"Defined TRIM22 as a bona fide RING-dependent antiviral restriction factor and an active E3 ligase, answering whether its catalytic domain underlies function.","evidence":"VLP budding and Gag localization assays with RING C15A/C18A mutants for HIV-1; in vitro reconstitution with UbcH5B and in vivo self-ubiquitylation for ligase activity","pmids":["18389079","18656448"],"confidence":"High","gaps":["Direct ubiquitin substrate for HIV Gag trafficking disruption not pinned down","Whether self-ubiquitylation regulates antiviral output unclear"]},{"year":2009,"claim":"Showed that the SPRY/B30.2 domain and subcellular targeting determine TRIM22 behavior, with species-specific localization and constitutive centrosomal positioning.","evidence":"Domain-swap and VL1/VL3 mutational imaging across human/rhesus TRIM22; immunofluorescence of endogenous protein at centrosomes with microtubule depolymerization","pmids":["19212762","20006605"],"confidence":"Medium","gaps":["Functional consequence of centrosomal localization not demonstrated","Link between localization and antiviral specificity unestablished"]},{"year":2009,"claim":"Demonstrated that TRIM22 antiviral activity against ECMV requires E3 ligase function and direct engagement of a viral substrate, generalizing the degradation model beyond HIV.","evidence":"Antiviral protection assay, Co-IP with 3C protease, ubiquitination assay, and RING deletion in HeLa cells","pmids":["19218198"],"confidence":"High","gaps":["Ubiquitin chain linkage on 3C^PRO not characterized","Domain mediating 3C^PRO recognition not mapped"]},{"year":2011,"claim":"Separated TRIM22's transcriptional silencing of the HIV-1 LTR from its catalytic activity, revealing a ligase-independent mode of antiviral action.","evidence":"Stable KD and transduction across cell systems, LTR-luciferase reporters with NF-κB site deletions, and E3-dead RING mutant analysis","pmids":["21345949"],"confidence":"High","gaps":["Mechanism of transcriptional repression not yet identified at this stage","Nuclear cofactors unknown"]},{"year":2011,"claim":"Identified upstream control of TRIM22 expression, showing chromatin remodeling is required for IFN-γ-driven induction via IRF-1.","evidence":"BRG1-deficient cells with reconstitution, ChIP of IRF-1 at the TRIM22 promoter, and BRG1 ATPase-domain mutants","pmids":["21683060"],"confidence":"Medium","gaps":["Whether BRG1 acts directly or via accessory remodelers unresolved","Single isogenic cell-line system"]},{"year":2011,"claim":"Implicated TRIM22 as a positive regulator of NF-κB and inflammatory cytokine output, opening a non-antiviral signaling role.","evidence":"NF-κB luciferase reporter, EMSA, domain deletion mutants, and cytokine ELISA in U937 macrophages","pmids":["21651891"],"confidence":"Medium","gaps":["Direct molecular target in the NF-κB pathway not identified here","Single study"]},{"year":2013,"claim":"Extended the substrate-degradation model to influenza A NP and revealed context-dependent NF-κB roles via TAB2 degradation.","evidence":"Co-IP, ubiquitination and proteasome-rescue assays for NP in MDCK cells; Co-IP and degradation of TAB2 with RING mutant for TRAF6/NF-κB","pmids":["23408607","23818111"],"confidence":"Medium","gaps":["Reconciliation of NF-κB activation versus TAB2-mediated inhibition not addressed","Ubiquitin linkage types not all defined"]},{"year":2015,"claim":"Mechanistically resolved LTR silencing as blockade of Sp1 promoter binding and broadened restriction to HCV NS5A.","evidence":"Sp1-site reporter deletions, protein-DNA pulldown and ChIP for Sp1 displacement; NS5A ubiquitination and replication assays with TRIM22 KD/OE in Huh-7","pmids":["26683615","25683609"],"confidence":"High","gaps":["How nuclear TRIM22 is recruited to the LTR without binding Sp1 unresolved","NS5A ubiquitination linkage and degradation route not fully defined"]},{"year":2015,"claim":"Diversified TRIM22 signaling roles to noncanonical NF-κB activation, translational repression, and autophagosomal turnover of a transcription factor.","evidence":"Co-IP and p100/p52 processing with IKKα; eIF4E/eIF4G competition and translation assays; FoxO4 lysosomal degradation with IFN-β reporter and apoptosis assays","pmids":["25510414","22509910","26237181"],"confidence":"Medium","gaps":["Whether these activities operate in the same cell types simultaneously unclear","Several rely on single-lab indirect readouts"]},{"year":2016,"claim":"Connected TRIM22 to human disease, showing patient variants disrupt NOD2-dependent IFN-β and NF-κB signaling in very-early-onset IBD.","evidence":"Whole-exome sequencing with functional studies in patient cells showing impaired NOD2/IFN-β/NF-κB signaling","pmids":["26836588"],"confidence":"Medium","gaps":["Direct biochemical mechanism linking TRIM22 to NOD2 not defined","Single report"]},{"year":2017,"claim":"Revealed promoter-level immune evasion and pro-apoptotic functions, defining how viral and host factors tune TRIM22 abundance and outputs.","evidence":"Bisulfite sequencing and IRF-1 binding for HBx-driven CpG methylation in mouse and primary hepatocytes; domain-mutant apoptosis and Bak oligomerization assays in monocytes","pmids":["28341749","28079123"],"confidence":"High","gaps":["Mechanism by which TRIM22 promotes Bak oligomerization not biochemically defined","Generality of single-CpG control across tissues unknown"]},{"year":2020,"claim":"Established TRIM22 as an oncogenic NF-κB driver in glioblastoma through dual K48/K63 ubiquitination events, demonstrating in vivo relevance.","evidence":"Reciprocal Co-IP, linkage-specific ubiquitination of IκBα and IKKγ-complex, RING mutant, NF-κB reporter, and orthotopic xenograft","pmids":["32814880"],"confidence":"High","gaps":["Reconciliation with reports of TRIM22 inhibiting NF-κB via TAB2 unresolved","Tissue determinants of pro- versus anti-NF-κB activity unknown"]},{"year":2022,"claim":"Expanded the substrate repertoire to redox and senescence regulators (NRF2, PHLPP2) and an additional flavivirus restriction (ZIKV), refining domain-specific recognition and catalysis.","evidence":"Co-IP, ubiquitination and E3-mutant assays plus rescue/in vivo for NRF2 and PHLPP2; SPRY-binding/RING-degradation mapping for ZIKV NS1/NS3 with KO infectivity","pmids":["35636015","38199981","36042495"],"confidence":"High","gaps":["NRF2 ubiquitination linkage type not fully specified","Why some substrates require prior phosphorylation for SPRY recognition unclear"]},{"year":2023,"claim":"Defined TRIM22 as an E3-independent autophagy scaffold and extended MAPK-driven oncogenesis, with a familial Alzheimer variant impairing autophagic clearance.","evidence":"Co-IP, PLA, and autophagy-flux assays with E3-dead mutant for GABARAP-PLEKHM1 bridging; Co-IP with domain mapping and xenograft for Raf-1 degradation/MAPK in GBM","pmids":["38009729","37258577"],"confidence":"High","gaps":["How the scaffolding and ligase activities are coordinated in cells unresolved","Raf-1 study is single-lab Medium-confidence"]},{"year":2024,"claim":"Broadened catalytic versatility to non-canonical linkages and additional substrates, showing K48 (NSP8), K27 (CCS), and stabilizing non-K48 ubiquitination (Bcl-2) tied to distinct outcomes.","evidence":"Site-specific ubiquitination mutants (NSP8 K97, CCS K76) with domain mapping and functional readouts; ubiquitination microarray and Co-IP for Bcl-2 stabilization","pmids":["38275298","39127340","40552115"],"confidence":"High","gaps":["Determinants selecting different chain linkages on different substrates unknown","Bcl-2 stabilization mechanism is single-lab Medium-confidence"]},{"year":2025,"claim":"Integrated TRIM22 into the RIG-I/MAVS innate signaling axis as a K63-MAVS ubiquitin ligase, and fully delineated its multidomain autophagy-initiation scaffold function.","evidence":"K63-specific MAVS ubiquitination with KO/IFN-β reporters and ELF3 promoter ChIP; domain-deletion Co-IP and competitive-binding autophagy-flux assays for ULK1/ATG13/FIP200/Beclin-1 assembly","pmids":["40162781","40337095"],"confidence":"High","gaps":["Spatial/temporal switch between MAVS amplification and substrate degradation unresolved","Whether scaffold and ligase domains act on overlapping complexes in vivo unclear"]},{"year":null,"claim":"It remains unresolved what governs TRIM22's context-dependent choice among catalytic versus scaffold modes, ubiquitin-chain linkage selection, and opposing pro- versus anti-tumorigenic and pro- versus anti-NF-κB outcomes across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking domain architecture to mode selection","Conflicting NF-κB and oncogenic/tumor-suppressive roles not mechanistically reconciled","In vivo physiological substrate hierarchy unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,4,15,16,17,18,34]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,15,17,18,34,48]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,15,16,18,34]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[29,37]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,13,36]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,6,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,17,18,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,20,33,36]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[29,37,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,15,16,17,18,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,29]}],"complexes":["ULK1-ATG13-FIP200-ATG101 autophagy initiation complex","class III PI3K (Beclin-1) complex"],"partners":["MAVS","GABARAP","PLEKHM1","BECLIN-1","IKKGAMMA","RAF-1","PHLPP2","ATG13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYM9","full_name":"E3 ubiquitin-protein ligase TRIM22","aliases":["50 kDa-stimulated trans-acting factor","RING finger protein 94","RING-type E3 ubiquitin transferase TRIM22","Staf-50","Tripartite motif-containing protein 22"],"length_aa":498,"mass_kda":56.9,"function":"Interferon-induced E3 ubiquitin ligase that plays important roles in innate and adaptive immunity (PubMed:25683609, PubMed:35777501). Restricts the replication of many viruses including HIV-1, encephalomyocarditis virus (EMCV), hepatitis B virus (HBV), hepatitis C virus (HCV) or Zika virus (ZIKV) (PubMed:25683609, PubMed:35777501, PubMed:36042495). Mechanistically, negatively regulates HCV replication by promoting ubiquitination and subsequent degradation of viral NS5A (PubMed:25683609). Also acts by promoting the degradation of Zika virus NS1 and NS3 proteins through proteasomal degradation (PubMed:36042495). Acts as a suppressor of basal HIV-1 LTR-driven transcription by preventing Sp1 binding to the HIV-1 promoter (PubMed:26683615). Also plays a role in antiviral immunity by co-regulating together with NT5C2 the RIGI/NF-kappa-B pathway by promoting 'Lys-63'-linked ubiquitination of RIGI, while NT5C2 is responsible for 'Lys-48'-linked ubiquitination of RIGI (PubMed:36159777). Participates in adaptive immunity by suppressing the amount of MHC class II protein in a negative feedback manner in order to limit the extent of MHC class II induction (PubMed:35777501)","subcellular_location":"Cytoplasm; Nucleus; Nucleus speckle; Nucleus, Cajal body","url":"https://www.uniprot.org/uniprotkb/Q8IYM9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM22","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/TRIM22","total_profiled":1310},"omim":[{"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":"606559","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 22; TRIM22","url":"https://www.omim.org/entry/606559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM22"},"hgnc":{"alias_symbol":["STAF50","GPSTAF50","RNF94"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYM9","domains":[{"cath_id":"3.30.40.10","chopping":"4-87","consensus_level":"high","plddt":82.8795,"start":4,"end":87},{"cath_id":"2.60.120.920","chopping":"287-330_340-375_400-495","consensus_level":"high","plddt":90.213,"start":287,"end":495},{"cath_id":"1.20.5","chopping":"137-262","consensus_level":"medium","plddt":94.2032,"start":137,"end":262}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYM9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYM9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYM9-F1-predicted_aligned_error_v6.png","plddt_mean":85.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM22","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM22"},"sequence":{"accession":"Q8IYM9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYM9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYM9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYM9"}},"corpus_meta":[{"pmid":"18389079","id":"PMC_18389079","title":"The interferon response inhibits HIV particle production by induction of TRIM22.","date":"2008","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/18389079","citation_count":232,"is_preprint":false},{"pmid":"23408607","id":"PMC_23408607","title":"TRIM22 inhibits influenza A virus infection by targeting the viral nucleoprotein for degradation.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23408607","citation_count":210,"is_preprint":false},{"pmid":"35636015","id":"PMC_35636015","title":"TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/35636015","citation_count":151,"is_preprint":false},{"pmid":"18159944","id":"PMC_18159944","title":"Discordant evolution of the adjacent antiretroviral genes TRIM22 and TRIM5 in mammals.","date":"2007","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/18159944","citation_count":142,"is_preprint":false},{"pmid":"32814880","id":"PMC_32814880","title":"TRIM22 activates NF-κB signaling in glioblastoma by accelerating the degradation of IκBα.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/32814880","citation_count":129,"is_preprint":false},{"pmid":"19218198","id":"PMC_19218198","title":"TRIM22 E3 ubiquitin ligase activity is required to mediate antiviral activity against encephalomyocarditis virus.","date":"2009","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/19218198","citation_count":104,"is_preprint":false},{"pmid":"26836588","id":"PMC_26836588","title":"Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.","date":"2016","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26836588","citation_count":97,"is_preprint":false},{"pmid":"21345949","id":"PMC_21345949","title":"TRIM22 inhibits HIV-1 transcription independently of its E3 ubiquitin ligase activity, Tat, and NF-kappaB-responsive long terminal repeat elements.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21345949","citation_count":92,"is_preprint":false},{"pmid":"25683609","id":"PMC_25683609","title":"Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A.","date":"2015","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25683609","citation_count":83,"is_preprint":false},{"pmid":"15064739","id":"PMC_15064739","title":"Staf50 is a novel p53 target gene conferring reduced clonogenic growth of leukemic U-937 cells.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15064739","citation_count":67,"is_preprint":false},{"pmid":"20980524","id":"PMC_20980524","title":"Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection.","date":"2010","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/20980524","citation_count":66,"is_preprint":false},{"pmid":"26683615","id":"PMC_26683615","title":"HIV-1 transcriptional silencing caused by TRIM22 inhibition of Sp1 binding to the viral promoter.","date":"2015","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/26683615","citation_count":63,"is_preprint":false},{"pmid":"28341749","id":"PMC_28341749","title":"Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5'-UTR of 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genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41118115","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54733,"output_tokens":12498,"usd":0.175835,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23798,"output_tokens":6054,"usd":0.13517,"stage2_stop_reason":"end_turn"},"total_usd":0.311005,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM22 inhibits HIV-1 particle release by targeting HIV Gag, disrupting its trafficking to the plasma membrane; the RING domain catalytic residues Cys15 and Cys18 are required for this antiviral activity. TRIM22 does not block MLV or EIAV Gag particle release, indicating specificity for HIV Gag.\",\n      \"method\": \"RNAi knockdown, overexpression, virus-like particle budding assay, mutational analysis of RING domain (C15A/C18A), fluorescence microscopy of Gag localization\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, OE, mutagenesis, imaging), independently replicated concept across multiple labs\",\n      \"pmids\": [\"18389079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM22 is a functional E3 ubiquitin ligase that catalyzes self-ubiquitylation in vitro in combination with E2 enzyme UbcH5B, dependent on its RING finger domain; TRIM22 also undergoes self-ubiquitylation in vivo and is targeted for proteasomal degradation via poly-ubiquitin chains. TRIM22 localizes to the nucleus.\",\n      \"method\": \"In vitro ubiquitylation assay with UbcH5B, in vivo ubiquitylation in 293T cells, proteasome inhibitor stabilization assay, subcellular fractionation/localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of E3 activity with E2, in vivo confirmation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18656448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRIM22 E3 ubiquitin ligase activity is required for antiviral protection against encephalomyocarditis virus (ECMV); TRIM22 interacts with the viral 3C protease (3C^PRO) and mediates its ubiquitination. A RING domain deletion mutant abolishes both E3 activity and antiviral effect.\",\n      \"method\": \"Antiviral protection assay in HeLa cells, co-immunoprecipitation of TRIM22 with 3C^PRO, ubiquitination assay, RING deletion mutant analysis\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and domain mutant with functional readout in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19218198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM22 inhibits HIV-1 LTR-driven transcription independently of its E3 ubiquitin ligase activity, Tat transactivation, and NF-κB binding sites in the LTR. Nuclear TRIM22 suppresses basal and phorbol ester-induced HIV-1 transcription.\",\n      \"method\": \"Stable TRIM22 knockdown in U937 cells, TRIM22 transduction in permissive cells, LTR-luciferase reporter assays with NF-κB site deletion constructs, RING mutant (E3-dead) analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell systems, reporter assays with deletion constructs, E3-dead mutant, replicated concept in subsequent studies\",\n      \"pmids\": [\"21345949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM22 restricts influenza A virus (IAV) replication by interacting with the viral nucleoprotein (NP) and promoting its polyubiquitination and proteasome-dependent degradation.\",\n      \"method\": \"shRNA knockdown, overexpression in MDCK cells, Co-IP of TRIM22 with NP, ubiquitination assay, proteasome inhibitor rescue, viral titer measurement\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome inhibitor rescue, KD and OE with functional readout, single lab multiple orthogonal methods\",\n      \"pmids\": [\"23408607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM22 activates NF-κB in a dose-dependent manner; both the N-terminal RING domain and C-terminal SPRY domain are required for NF-κB activation. TRIM22 overexpression induces pro-inflammatory cytokine secretion in U937 macrophages in an NF-κB-dependent manner.\",\n      \"method\": \"NF-κB luciferase reporter assay, EMSA, domain deletion mutants, cytokine ELISA\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter assay and EMSA with domain mutants, single lab, single study\",\n      \"pmids\": [\"21651891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM22 inhibits HIV-1 LTR-driven transcription by preventing Sp1 binding to the viral promoter; TRIM22 does not interact directly with Sp1 but blocks Sp1 binding as shown by protein-DNA pulldown and chromatin immunoprecipitation.\",\n      \"method\": \"Reporter assays with Sp1-binding-site deletion constructs in 293T cells, TRIM22 KD in SupT1 T cells with HIV replication assay, protein-DNA pulldown, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and protein-DNA pulldown showing TRIM22 blocks Sp1 binding, reporter assays, KD phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26683615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM22 ubiquitinates HCV NS5A protein in a concentration-dependent manner, and TRIM22 expression inhibits HCV replication; siRNA-mediated TRIM22 knockdown diminishes IFNα-induced anti-HCV function.\",\n      \"method\": \"TRIM22 overexpression and siRNA knockdown in Huh-7 cells, HCV replication assay, NS5A ubiquitination assay\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination assay and KD/OE with functional readout, single lab\",\n      \"pmids\": [\"25683609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM22 inhibits the TRAF6-stimulated NF-κB pathway by interacting with and degrading TAB2 in a RING domain-dependent manner; TRIM22 also decreases TRAF6 self-ubiquitination.\",\n      \"method\": \"NF-κB reporter assay, Co-IP of TRIM22 with TAB2, TAB2 degradation assay with RING deletion mutant, TRAF6 ubiquitination assay\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and degradation assay with domain mutant, single lab\",\n      \"pmids\": [\"23818111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRIM22 (Staf50) is a direct p53 target gene; a functional p53-response element in intron 1 mediates direct p53 binding (shown by EMSA) and transactivation; p53-family member p73 also transactivates via this element. Ectopic TRIM22 expression reduces clonogenic growth of U937 leukemic cells.\",\n      \"method\": \"cDNA microarray, cycloheximide chase (independence of de novo protein synthesis), EMSA, luciferase reporter assay with intron 1 p53-RE, ectopic expression clonogenic assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA showing direct p53 binding, reporter assay, functional growth assay, multiple orthogonal methods\",\n      \"pmids\": [\"15064739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human and rhesus TRIM22 localize to different subcellular compartments, and this difference maps to the B30.2/SPRY domain; amino acid changes in variable loops VL1 and VL3 of the B30.2 domain are responsible for the species-specific subcellular localization differences.\",\n      \"method\": \"Fluorescence microscopy of GFP-tagged constructs, domain swap/chimeric protein experiments, mutational analysis of VL1 and VL3\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by imaging with domain mutants, single lab\",\n      \"pmids\": [\"19212762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Endogenous TRIM22 colocalizes with centrosomes independently of cell cycle phase in primary human mononuclear cells and U2OS cells, and this colocalization is independent of the microtubule network.\",\n      \"method\": \"Immunofluorescence of endogenous TRIM22 with centrosome markers, microtubule depolymerization experiment, cell cycle staging\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct localization imaging, single lab, no functional consequence demonstrated\",\n      \"pmids\": [\"20006605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM22 directly or indirectly interacts with translation initiation factor eIF4E and inhibits eIF4E binding to eIF4G, thereby disrupting eIF4F complex assembly and repressing cap-dependent translation of specific mRNAs including IRF-7C.\",\n      \"method\": \"Co-immunoprecipitation of TRIM22 with eIF4E, eIF4G binding competition assay, luciferase reporter assay, radiolabelled methionine incorporation assay\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP, functional translation assay, single lab\",\n      \"pmids\": [\"22509910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM22 activates the noncanonical NF-κB pathway by interacting with IKKα (but not IKKβ) via its RING and SPRY domains, increasing IKKα levels and phosphorylation, and inducing p100 processing to p52.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, Western blot for p100/p52 processing and IKKα phosphorylation, domain deletion mutants\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and co-localization with domain mutants, single lab\",\n      \"pmids\": [\"25510414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM22 variants disrupt the ability of TRIM22 to regulate NOD2-dependent activation of IFN-β signaling and NF-κB, establishing TRIM22 as a regulator of the NOD2 signaling pathway in a disease context (very-early-onset IBD).\",\n      \"method\": \"Whole-exome sequencing, functional studies in primary patient cells and cell culture showing disrupted NOD2/IFN-β/NF-κB signaling by TRIM22 variants\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional cell studies with patient-derived variants, single lab report\",\n      \"pmids\": [\"26836588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM22 promotes NF-κB signaling in GBM by: (1) binding IκBα and accelerating its degradation via K48-linked ubiquitination; (2) forming a complex with IKKγ and promoting K63-linked ubiquitination leading to IKKα/β and IκBα phosphorylation. RING domain E3 ligase activity is required for these effects. A non-phosphorylatable IκBα mutant (srIκBα) blocks TRIM22 growth-promoting activity.\",\n      \"method\": \"Co-immunoprecipitation, K48/K63-linked ubiquitination assays, Cas9-sgRNA knockout, RING mutant (C15/18A) and deletion analysis, NF-κB luciferase reporter, orthotopic xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, linkage-specific ubiquitination assays, RING mutant, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"32814880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM22 promotes proteasomal degradation of NRF2 via E3 ligase-dependent ubiquitination that is independent of KEAP1, reducing intracellular antioxidant capacity and activating ROS/AMPK/mTOR/autophagy signaling to induce autophagic cell death in osteosarcoma.\",\n      \"method\": \"Co-immunoprecipitation of TRIM22 with NRF2, ubiquitination assay, E3 ligase mutant analysis, ROS measurement, AMPK/mTOR pathway Western blot, in vitro and in vivo gain/loss-of-function with rescue by NRF2 manipulation or NAC/3-MA\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, E3 mutant, rescue experiments, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"35636015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM22 suppresses Zika virus (ZIKV) replication by interacting with viral NS1 and NS3 proteins and promoting their ubiquitination and proteasomal degradation; the SPRY domain mediates protein interaction and the RING domain mediates degradation. TRIM22 also inhibits dengue and yellow fever virus.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain deletion analysis (SPRY and RING), overexpression and TRIM22 KO cell infectivity assay, proteasome inhibitor rescue\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, domain-specific mutants, ubiquitination assay, KO functional assay, single lab multiple orthogonal methods\",\n      \"pmids\": [\"36042495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM22 E3 ubiquitin ligase promotes proteasomal degradation of SARS-CoV-2 NSP8 via K48-type ubiquitination at Lys97, thereby restricting viral replication; TRIM22 expression is induced by interferon signaling upon SARS-CoV-2 infection.\",\n      \"method\": \"Co-immunoprecipitation of TRIM22 with NSP8, K48-ubiquitination assay with site-specific Lys97 mutation, TRIM22 overexpression and knockdown viral replication assay\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination mutant (K97), KD and OE with viral readout, single lab multiple orthogonal methods\",\n      \"pmids\": [\"38275298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM22 induces cellular senescence in hepatocellular carcinoma by targeting PHLPP2 for proteasomal degradation via the SPRY domain binding PHLPP2's C-terminal IKKβ-phosphorylated domain; PHLPP2 degradation activates AKT-p53-p21 signaling leading to senescence.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, ubiquitination assay, IKKβ phosphorylation analysis, AKT/p53/p21 Western blot, cellular senescence assays (β-galactosidase, SAHF), p53 ChIP for TRIM22 promoter\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific Co-IP, ubiquitination, phosphorylation-dependent mechanism, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38199981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM22 promotes GBM proliferation by activating MAPK signaling; it binds Raf-1 (a negative regulator) via CC and SPRY domains and accelerates Raf-1 degradation by K48-linked ubiquitination (interaction requires Raf-1 C1D domain). TRIM22 also binds the SPHK2 gene at exon 2 to regulate SPHK2 transcription.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, K48-ubiquitination assay, ERK1/2 luciferase reporter, TRIM22 KO and OE, RING domain and NLS deletion mutants, in vivo xenograft\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with domain mutants, ubiquitination assay, single lab\",\n      \"pmids\": [\"37258577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM22 ubiquitinates FoxO4 and targets it for degradation via the autophagosomal-lysosomal (not ubiquitin-proteasome) pathway; this antagonizes FoxO4's role in promoting IFN-β expression downstream of TLR3/RIG-I activation. TRIM22 knockdown sensitizes cells to dsRNA-induced caspase-dependent apoptosis and suppresses Bcl-2.\",\n      \"method\": \"TRIM22 KD with poly(I:C) stimulation, FoxO4 KD, IFN-β reporter assay, assessment of FoxO4 protein levels, apoptosis assay (caspase activation), Bcl-2 Western blot\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect evidence for lysosomal degradation pathway, reporter and apoptosis assay, single lab\",\n      \"pmids\": [\"26237181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HBV X protein (HBx) suppresses TRIM22 transcription through a single CpG methylation in the TRIM22 5'-UTR, which reduces IRF-1 binding affinity to the TRIM22 promoter, thereby enabling HBV to evade innate immune restriction.\",\n      \"method\": \"LC-MS/MS proteomics, bisulfite sequencing for CpG methylation, IRF-1 binding assay, mouse model, primary human hepatocytes\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation mapped to single CpG, IRF-1 binding assay, validated in mouse model and primary cells, multiple orthogonal methods\",\n      \"pmids\": [\"28341749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRG1 (chromatin remodeling ATPase) is required for IFN-γ-induced TRIM22 expression; BRG1 deficiency does not impair IFN-γ-induced IRF-1 expression but blocks IRF-1 access to the TRIM22 promoter; BRG1 ATPase domain is required for TRIM22 induction and IRF-1 recruitment.\",\n      \"method\": \"BRG1-deficient SW-13 cell line with BRG1 reconstitution, ChIP of IRF-1 at TRIM22 promoter, BRG1 ATPase domain mutant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP with domain mutant, single lab, isogenic cell line system\",\n      \"pmids\": [\"21683060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p300, but not PCAF, functions as a transcriptional co-activator of IRF-1 for IFN-γ-induced TRIM22 expression independently of p300's histone acetyltransferase activity; p300 is required for RNA polymerase II recruitment to the TRIM22 promoter.\",\n      \"method\": \"In vitro DNA affinity binding assay, ChIP of p300 and RNA Pol II at TRIM22 promoter, p300 overexpression and knockdown, HAT-dead p300 mutant\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP, in vitro binding, HAT-dead mutant, single lab\",\n      \"pmids\": [\"23670564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM22 is a progesterone-receptor (PR) direct target gene; PR binds a progesterone response element (PRE) in the TRIM22 promoter region (-25 to -11 bp upstream of exon 1) in a hormone-dependent manner, and this PRE has enhancer activity.\",\n      \"method\": \"ChIP of PR at TRIM22 PRE, luciferase reporter assay for PRE activity, PR-stable Ishikawa cell clones, hormone-dependent TRIM22 expression\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and reporter assay for direct transcriptional regulation, single lab\",\n      \"pmids\": [\"26316153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM22 maintains HIV-1 proviral latency in T cell lines; TRIM22 knockdown accelerates reactivation of a dox-controlled HIV-1 in SupT1 cells and potentiates HIV-1 expression in ACH-2 and J-Lat 10.6 cell lines upon TNF-α or HDAC inhibitor stimulation.\",\n      \"method\": \"TRIM22 knockdown in T cell lines, dox-controlled HIV-1 replication system, TNF-α/HDACi stimulation, HIV-1 p24 and luciferase readouts\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined functional readout in multiple T cell lines, single lab\",\n      \"pmids\": [\"31136823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM22 interacts with PRRSV nucleocapsid (N) protein through its SPRY domain; the NLS2 motif of N protein is involved in the interaction with TRIM22. The NLS (nuclear localization signal) and SPRY domain of TRIM22 are both required for inhibition of PRRSV replication; however, PRRSV N protein levels are not altered by TRIM22, whereas N proteins from related arteriviruses (SHFV, EAV, LDV) are reduced by TRIM22 overexpression.\",\n      \"method\": \"Co-IP, TRIM22 domain deletion constructs (ΔSPRY, ΔNLS), ectopic expression and RNAi in MARC-145 cells, viral titer measurement\",\n      \"journal\": \"Virus genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with domain mapping, single lab\",\n      \"pmids\": [\"31375995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM22 restricts HSV-1 replication by increasing histone occupancy and heterochromatin on viral immediate-early gene promoters, thereby reducing viral IE gene expression; this represents an epigenetic restriction mechanism independent of ICP0-mediated degradation.\",\n      \"method\": \"TRIM22 KO and overexpression, ChIP for histone occupancy and heterochromatin marks at viral IE promoters, ICP0-null and wild-type virus comparison, viral gene expression analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with KO/OE, ICP0-null vs WT comparison, mechanistic epigenetic readout, single lab multiple orthogonal methods\",\n      \"pmids\": [\"33524065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, independently of its E3 ubiquitin ligase activity; a TRIM22 variant associated with familial Alzheimer disease interferes with this function and impairs autophagic clearance.\",\n      \"method\": \"Co-IP, proximity ligation assay, TRIM22 KO with autophagy flux assay, E3 ligase-dead mutant analysis, Alzheimer variant functional testing in cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PLA, KO with functional autophagy readout, E3-dead mutant, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38009729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM22 promotes PRRSV N protein degradation through the lysosomal pathway by interacting with LC3; PRRSV miR-376b-3p directly targets TRIM22 to impair its anti-PRRSV activity.\",\n      \"method\": \"Co-IP of TRIM22 with PRRSV N protein and LC3, lysosomal pathway inhibitor experiments, miRNA target validation, viral replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with lysosomal pathway inhibitors, single lab\",\n      \"pmids\": [\"34757838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM22 mediates apoptosis in monocytes by promoting Bak expression and oligomerization; both the RING and SPRY domains are required. TRIM22 overexpression activates caspase-9 and caspase-3.\",\n      \"method\": \"TRIM22 overexpression in THP-1 and primary monocytes, domain deletion mutants (ΔRING, ΔSPRY), caspase activation assay, Bak oligomerization analysis by native PAGE/fractionation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — domain mutants with functional apoptosis readout, single lab\",\n      \"pmids\": [\"28079123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM22 forms a complex with NT5C2 in GBM and differentially regulates RIG-I ubiquitination: TRIM22 promotes K63-linked ubiquitination of RIG-I while NT5C2 promotes K48-linked ubiquitination, regulating the RIG-I/NF-κB/CCAR1 signaling axis.\",\n      \"method\": \"Co-IP, K48/K63-specific ubiquitination assays, TRIM22 KO with RIG-I ubiquitination readout, luciferase reporter, in vivo xenograft\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, linkage-specific ubiquitination assays, single lab\",\n      \"pmids\": [\"36159777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM22 interacts with PHLPP2 (AKT phosphatase) and induces its proteasomal degradation, leading to AKT activation and cellular senescence via AKT-p53-p21 signaling; IKKβ-mediated phosphorylation of PHLPP2's C-terminal domain is a prerequisite for TRIM22-SPRY-domain-mediated recognition.\",\n      \"method\": \"Co-IP with SPRY domain mapping, ubiquitination assay, IKKβ phosphorylation analysis, AKT/p53/p21 Western blot, β-galactosidase and SAHF senescence assays, TRIM22 KO/OE\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific Co-IP, phospho-dependent ubiquitination, multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"38199981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM22 ubiquitinates copper chaperone CCS via K27-linked ubiquitination at CCS Lys76, requiring the TRIM22 coiled-coil domain; CCS degradation suppresses STAT3 phosphorylation by increasing ROS, inhibiting breast cancer proliferation and invasion.\",\n      \"method\": \"Label-free proteomics, Co-IP, ubiquitination assay with linkage-specific antibodies, site-directed mutagenesis (K76R of CCS), TRIM22 coiled-coil domain deletion mutant, ChIP-qPCR, ROS measurement, RNA-seq GSEA\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific Co-IP, site-specific ubiquitination mutant, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39127340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP promotes m6A modification of TRIM22 5'UTR via the m6A reader IGF2BP1, increasing TRIM22 expression; TRIM22 then interacts with OPA1 and induces its ubiquitination, causing mitochondrial dysfunction in diabetic nephropathy.\",\n      \"method\": \"RNA immunoprecipitation for m6A detection of TRIM22 5'UTR, Co-IP of TRIM22 with OPA1, ubiquitination assay, mitochondrial function assays\",\n      \"journal\": \"Redox report\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and RIP assay, single lab\",\n      \"pmids\": [\"39314036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 enhances RIG-I-mediated antiviral signaling by catalyzing K63-linked polyubiquitination of MAVS, activating the TBK1/IRF3 pathway and IFN-β production; TRIM22 also inhibits the MAVS-NLRX1 inhibitory complex assembly. RNA virus infection induces TRIM22 expression via nuclear translocation of transcription factor ELF3, which activates TRIM22 gene transcription.\",\n      \"method\": \"Co-IP, K63-specific ubiquitination assay of MAVS, TRIM22 KO/KD with IFN-β reporter and TBK1/IRF3 phosphorylation assay, ELF3 nuclear translocation and ChIP/reporter assay for TRIM22 promoter, MAVS-NLRX1 Co-IP\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K63-ubiquitination assay, KO functional readout, promoter ChIP, multiple pathways assessed, multiple orthogonal methods\",\n      \"pmids\": [\"40162781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 functions as a scaffold protein for autophagy initiation: SPRY domain mediates interaction with ATG13 and FIP200; N-terminal region interacts with ULK1 and ATG101; B-box domain is required for interaction with Beclin-1 and assembly of the class III PI3K complex; Beclin-1 and PLEKHM1 compete for overlapping TRIM22 binding regions. This function is independent of E3 ubiquitin ligase activity.\",\n      \"method\": \"Co-IP with domain deletion constructs, competitive binding assay, autophagy flux assay (LC3-II, autophagic clearance), TRIM22 KO, mTOR/AMPK activity measurement, primary neuron experiments\",\n      \"journal\": \"Animal cells and systems\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific Co-IP, competitive binding, E3-dead mutant, KO with autophagic flux readout, multiple orthogonal methods\",\n      \"pmids\": [\"40337095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM22 ubiquitinates TCF4 via K48-linked ubiquitination mediated by the TRIM22 RING domain, leading to TCF4 proteasomal degradation and suppression of ovarian cancer cell proliferation and invasion.\",\n      \"method\": \"Co-IP, ubiquitination assay with RING domain deletion mutant, rescue of TRIM22 phenotype by TCF4 overexpression\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination with domain mutant, single lab\",\n      \"pmids\": [\"38842601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 promotes K63-linked ubiquitination of p21 via its SPRY domain (interaction) and RING domain (catalysis), inducing p21 degradation through the proteasome pathway to accelerate cell cycle progression in melanoma.\",\n      \"method\": \"S-protein pulldown of p21 with TRIM22 SPRY domain, ubiquitination assay (K63-linked), CHX chase confirming proteasomal degradation, p21 KD epistasis experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pulldown, K63-ubiquitination assay, epistasis experiment, single lab\",\n      \"pmids\": [\"40593126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 ubiquitinates and degrades CDT2 (CRL4 subunit), acting as a novel E3 ligase for CDT2 in HPV-positive cervical cancer cells; E6-mediated p53 degradation downregulates TRIM22 (a p53 target), leading to CDT2 accumulation that promotes cancer cell growth and survival.\",\n      \"method\": \"Ubiquitination assay of CDT2 by TRIM22, Western blot and KD/OE for CDT2/TRIM22 relationship, epistasis with E6/E7, p53 transcription of TRIM22\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ubiquitination assay and KD, single lab\",\n      \"pmids\": [\"40680432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 interacts with KAT2A and promotes its ubiquitination-dependent degradation in melanoma cells; loss of TRIM22 allows KAT2A accumulation, which binds the Notch1 promoter to increase H3K9ac and activate Notch1 transcription, promoting cancer stemness.\",\n      \"method\": \"Co-IP, ubiquitination assay, ChIP of KAT2A at Notch1 promoter for H3K9ac, TRIM22 KO/OE, Notch1 inhibitor rescue\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP, ChIP with KO/OE, single lab\",\n      \"pmids\": [\"37415153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HOXC8 transcriptionally activates TRIM22 expression; TRIM22 then ubiquitinates and degrades IκBα, activating NF-κB signaling to drive stemness maintenance in colorectal cancer cells.\",\n      \"method\": \"Luciferase reporter and ChIP for HOXC8-TRIM22 promoter interaction, ubiquitination assay of IκBα by TRIM22, NF-κB activity and stemness markers\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter, ChIP, and ubiquitination assay, single lab\",\n      \"pmids\": [\"41265630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 interacts with ADRB2 (β-2 adrenergic receptor) and negatively regulates ADRB2 expression and JAK2/STAT3 signaling in lung adenocarcinoma cells.\",\n      \"method\": \"STRING database prediction, co-immunoprecipitation of TRIM22 with ADRB2, ADRB2 and TRIM22 KD/OE with JAK2/STAT3 Western blot and cell proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP without mechanistic ubiquitination analysis, single lab\",\n      \"pmids\": [\"40594822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Constitutive TRIM22 expression in lung/respiratory tract epithelia (independent of IFN stimulation) is sufficient to restrict influenza A virus replication by inhibiting viral transcription onset, representing an intrinsic (pre-existing) defense.\",\n      \"method\": \"Transcriptomic analysis of human tissues, primary respiratory cell lines, rhesus macaque airway TRIM22 expression, TRIM22 KD with IAV replication assay (viral transcript measurement), comparison of IFN-dependent vs constitutive expression\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with viral transcription readout in primary cells and in vivo tissues, single lab\",\n      \"pmids\": [\"34621686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM22 negatively regulates MHC class II protein expression through a mechanism other than transcription or protein degradation; TRIM22 KO increases MHC-II protein levels while OE decreases them, without affecting CIITA or MHC-II mRNA levels.\",\n      \"method\": \"Cas9-sgRNA knockout and TRIM22 overexpression, Western blot for MHC-II protein and mRNA (qPCR), cycloheximide chase for MHC-II degradation\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KO/OE with protein level readout, mechanism not fully elucidated, single lab\",\n      \"pmids\": [\"35777501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 promotes GBM cell survival by stabilizing Bcl-2 via non-degradative (non-K48) ubiquitination; TRIM22 binds Bcl-2 and increases its protein expression levels.\",\n      \"method\": \"Immunoprecipitation of TRIM22-Bcl-2 complex, ubiquitination microarray, ubiquitination assay, Western blot, flow cytometry apoptosis assay\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab\",\n      \"pmids\": [\"40552115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM22 directly interacts with KAT2A and promotes KAT2A ubiquitination and degradation in hepatocellular carcinoma cells, reducing H3K9ac enrichment at the GPX4 promoter and promoting ferroptosis through the KAT2A/GPX4 axis; O-GlcNAcylation of KAT2A at S583 blocks TRIM22-mediated ubiquitination, stabilizing KAT2A.\",\n      \"method\": \"Co-IP of TRIM22 with KAT2A, ubiquitination assay, ChIP-qPCR for H3K9ac at GPX4 promoter, ferroptosis markers (Fe2+, MDA, ROS, GSH), O-GlcNAcylation site mutant (S583A), in vivo tumor model\",\n      \"journal\": \"Histology and histopathology / Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP, ChIP, ubiquitination, single lab each study\",\n      \"pmids\": [\"39698827\", \"42114931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM22 inhibits colorectal cancer metastasis by directly interacting with and ubiquitinating β-Catenin, promoting its degradation and inhibiting EMT; this anti-metastatic effect depends on TRIM22 E3 ligase activity.\",\n      \"method\": \"Co-IP of TRIM22 with β-Catenin, ubiquitination assay, TRIM22 OE/KD with β-Catenin rescue, in vivo metastasis model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination with rescue, single lab\",\n      \"pmids\": [\"39978715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM22 negatively regulates TLR3-induced CCL5 expression in human renal proximal tubular epithelial cells; TRIM22 is induced downstream of IFN-β in a TLR3-IFN-β-TRIM22 pathway, and its knockdown upregulates poly(I:C)-induced CCL5 production.\",\n      \"method\": \"siRNA knockdown of TRIM22 and IFN-β, poly(I:C) stimulation, TRIM22/CCL5/IFN-β mRNA and protein quantification in hRPTECs\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD with defined pathway and functional readout, single lab\",\n      \"pmids\": [\"40080304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM22 directly interacts with Smad2 in gastric cancer cells; overexpression of TRIM22 downregulates Smad2 phosphorylation and Smad3 phosphorylation; Smad2 overexpression reverses TRIM22-induced inhibition of proliferation and migration.\",\n      \"method\": \"Co-IP of TRIM22 with Smad2, Western blot for p-Smad2/3, rescue experiment with Smad2 overexpression, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with epistasis rescue, single lab\",\n      \"pmids\": [\"34489426\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM22 is an interferon-inducible, p53-regulated RING-type E3 ubiquitin ligase that restricts diverse viruses (HIV-1, IAV, ECMV, HCV, ZIKV, SARS-CoV-2, HSV-1) through multiple mechanisms: direct ubiquitination and proteasomal degradation of viral proteins (HIV Gag trafficking disruption, IAV NP, ECMV 3C^PRO, HCV NS5A, ZIKV NS1/NS3, SARS-CoV-2 NSP8); epigenetic silencing of the HIV-1 LTR by blocking Sp1 binding (E3-independent); K63-linked polyubiquitination of MAVS to amplify TBK1/IRF3/IFN-β signaling; and epigenetic deposition of heterochromatin on HSV-1 IE gene promoters. In cancer and non-viral settings, TRIM22 ubiquitinates numerous substrates (NRF2, IκBα, PHLPP2, Raf-1, TAB2, CCS, KAT2A, p21, β-Catenin, CDT2, OPA1, Bcl-2) to modulate NF-κB, MAPK, AKT, and autophagy signaling, and also acts as an E3-independent scaffold that promotes autophagosome–lysosome fusion (via GABARAP-PLEKHM1 bridging) and autophagy initiation (via ULK1/ATG13/FIP200/Beclin-1 complex assembly through distinct TRIM22 domains).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM22 is an interferon- and p53-inducible RING-type E3 ubiquitin ligase that acts as a broad antiviral restriction factor and, in non-viral settings, as a regulator of NF-κB, MAPK/AKT, and autophagy signaling [#9, #1, #15]. As an E3 ligase it self-ubiquitylates in vitro with the E2 UbcH5B through its RING domain and is itself degraded by the proteasome [#1]. Against viruses it engages diverse viral proteins—typically via its C-terminal SPRY/B30.2 domain—and targets them for RING-dependent ubiquitination and proteasomal degradation, including influenza A NP [#4], Zika NS1/NS3 [#17], and SARS-CoV-2 NSP8 (K48-linked at Lys97) [#18], while disrupting trafficking of HIV-1 Gag [#0] and ubiquitinating the picornaviral 3C protease and HCV NS5A [#2, #7]. TRIM22 also restricts viruses through ligase-independent mechanisms: it silences the HIV-1 LTR by blocking Sp1 occupancy of the promoter [#3, #6], maintains HIV-1 proviral latency [#26], and deposits heterochromatin on HSV-1 immediate-early promoters [#28]. It additionally amplifies innate signaling by catalyzing K63-linked polyubiquitination of MAVS to drive TBK1/IRF3/IFN-β output [#36]. In cancer and other non-viral contexts TRIM22 ubiquitinates numerous substrates—NRF2, IκBα, PHLPP2, Raf-1, CCS, β-Catenin—to modulate antioxidant, NF-κB, MAPK, AKT-p53-p21, and senescence programs [#16, #15, #19, #20, #34, #48]. Beyond its catalytic activity, TRIM22 serves as an E3-independent scaffold that promotes autophagosome–lysosome fusion by bridging GABARAP-family proteins to PLEKHM1 and nucleates autophagy initiation by assembling ULK1/ATG13/FIP200 and Beclin-1 PI3K complexes through distinct domains [#29, #37]. TRIM22 variants are linked to very-early-onset inflammatory bowel disease through disrupted NOD2-dependent signaling [#14] and to a familial Alzheimer disease phenotype through impaired autophagic clearance [#29]. Its own expression is controlled at the promoter by IRF-1 (with BRG1 and p300), p53, progesterone receptor, HOXC8, and ELF3, and is suppressed by HBV via 5'-UTR CpG methylation [#23, #24, #9, #25, #42, #36, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established TRIM22 as a directly transcriptionally regulated effector, placing it downstream of the p53 tumor-suppressor network and connecting it to growth control.\",\n      \"evidence\": \"cDNA microarray, EMSA, and reporter assays identifying a functional p53-response element in intron 1, with a clonogenic growth assay in leukemic cells\",\n      \"pmids\": [\"15064739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the ubiquitin-ligase substrates mediating growth suppression\", \"p73 contribution to physiological regulation unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined TRIM22 as a bona fide RING-dependent antiviral restriction factor and an active E3 ligase, answering whether its catalytic domain underlies function.\",\n      \"evidence\": \"VLP budding and Gag localization assays with RING C15A/C18A mutants for HIV-1; in vitro reconstitution with UbcH5B and in vivo self-ubiquitylation for ligase activity\",\n      \"pmids\": [\"18389079\", \"18656448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitin substrate for HIV Gag trafficking disruption not pinned down\", \"Whether self-ubiquitylation regulates antiviral output unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that the SPRY/B30.2 domain and subcellular targeting determine TRIM22 behavior, with species-specific localization and constitutive centrosomal positioning.\",\n      \"evidence\": \"Domain-swap and VL1/VL3 mutational imaging across human/rhesus TRIM22; immunofluorescence of endogenous protein at centrosomes with microtubule depolymerization\",\n      \"pmids\": [\"19212762\", \"20006605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of centrosomal localization not demonstrated\", \"Link between localization and antiviral specificity unestablished\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that TRIM22 antiviral activity against ECMV requires E3 ligase function and direct engagement of a viral substrate, generalizing the degradation model beyond HIV.\",\n      \"evidence\": \"Antiviral protection assay, Co-IP with 3C protease, ubiquitination assay, and RING deletion in HeLa cells\",\n      \"pmids\": [\"19218198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain linkage on 3C^PRO not characterized\", \"Domain mediating 3C^PRO recognition not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Separated TRIM22's transcriptional silencing of the HIV-1 LTR from its catalytic activity, revealing a ligase-independent mode of antiviral action.\",\n      \"evidence\": \"Stable KD and transduction across cell systems, LTR-luciferase reporters with NF-κB site deletions, and E3-dead RING mutant analysis\",\n      \"pmids\": [\"21345949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of transcriptional repression not yet identified at this stage\", \"Nuclear cofactors unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified upstream control of TRIM22 expression, showing chromatin remodeling is required for IFN-γ-driven induction via IRF-1.\",\n      \"evidence\": \"BRG1-deficient cells with reconstitution, ChIP of IRF-1 at the TRIM22 promoter, and BRG1 ATPase-domain mutants\",\n      \"pmids\": [\"21683060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BRG1 acts directly or via accessory remodelers unresolved\", \"Single isogenic cell-line system\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Implicated TRIM22 as a positive regulator of NF-κB and inflammatory cytokine output, opening a non-antiviral signaling role.\",\n      \"evidence\": \"NF-κB luciferase reporter, EMSA, domain deletion mutants, and cytokine ELISA in U937 macrophages\",\n      \"pmids\": [\"21651891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target in the NF-κB pathway not identified here\", \"Single study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the substrate-degradation model to influenza A NP and revealed context-dependent NF-κB roles via TAB2 degradation.\",\n      \"evidence\": \"Co-IP, ubiquitination and proteasome-rescue assays for NP in MDCK cells; Co-IP and degradation of TAB2 with RING mutant for TRAF6/NF-κB\",\n      \"pmids\": [\"23408607\", \"23818111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of NF-κB activation versus TAB2-mediated inhibition not addressed\", \"Ubiquitin linkage types not all defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mechanistically resolved LTR silencing as blockade of Sp1 promoter binding and broadened restriction to HCV NS5A.\",\n      \"evidence\": \"Sp1-site reporter deletions, protein-DNA pulldown and ChIP for Sp1 displacement; NS5A ubiquitination and replication assays with TRIM22 KD/OE in Huh-7\",\n      \"pmids\": [\"26683615\", \"25683609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear TRIM22 is recruited to the LTR without binding Sp1 unresolved\", \"NS5A ubiquitination linkage and degradation route not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Diversified TRIM22 signaling roles to noncanonical NF-κB activation, translational repression, and autophagosomal turnover of a transcription factor.\",\n      \"evidence\": \"Co-IP and p100/p52 processing with IKKα; eIF4E/eIF4G competition and translation assays; FoxO4 lysosomal degradation with IFN-β reporter and apoptosis assays\",\n      \"pmids\": [\"25510414\", \"22509910\", \"26237181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these activities operate in the same cell types simultaneously unclear\", \"Several rely on single-lab indirect readouts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected TRIM22 to human disease, showing patient variants disrupt NOD2-dependent IFN-β and NF-κB signaling in very-early-onset IBD.\",\n      \"evidence\": \"Whole-exome sequencing with functional studies in patient cells showing impaired NOD2/IFN-β/NF-κB signaling\",\n      \"pmids\": [\"26836588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism linking TRIM22 to NOD2 not defined\", \"Single report\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed promoter-level immune evasion and pro-apoptotic functions, defining how viral and host factors tune TRIM22 abundance and outputs.\",\n      \"evidence\": \"Bisulfite sequencing and IRF-1 binding for HBx-driven CpG methylation in mouse and primary hepatocytes; domain-mutant apoptosis and Bak oligomerization assays in monocytes\",\n      \"pmids\": [\"28341749\", \"28079123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TRIM22 promotes Bak oligomerization not biochemically defined\", \"Generality of single-CpG control across tissues unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established TRIM22 as an oncogenic NF-κB driver in glioblastoma through dual K48/K63 ubiquitination events, demonstrating in vivo relevance.\",\n      \"evidence\": \"Reciprocal Co-IP, linkage-specific ubiquitination of IκBα and IKKγ-complex, RING mutant, NF-κB reporter, and orthotopic xenograft\",\n      \"pmids\": [\"32814880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with reports of TRIM22 inhibiting NF-κB via TAB2 unresolved\", \"Tissue determinants of pro- versus anti-NF-κB activity unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the substrate repertoire to redox and senescence regulators (NRF2, PHLPP2) and an additional flavivirus restriction (ZIKV), refining domain-specific recognition and catalysis.\",\n      \"evidence\": \"Co-IP, ubiquitination and E3-mutant assays plus rescue/in vivo for NRF2 and PHLPP2; SPRY-binding/RING-degradation mapping for ZIKV NS1/NS3 with KO infectivity\",\n      \"pmids\": [\"35636015\", \"38199981\", \"36042495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NRF2 ubiquitination linkage type not fully specified\", \"Why some substrates require prior phosphorylation for SPRY recognition unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined TRIM22 as an E3-independent autophagy scaffold and extended MAPK-driven oncogenesis, with a familial Alzheimer variant impairing autophagic clearance.\",\n      \"evidence\": \"Co-IP, PLA, and autophagy-flux assays with E3-dead mutant for GABARAP-PLEKHM1 bridging; Co-IP with domain mapping and xenograft for Raf-1 degradation/MAPK in GBM\",\n      \"pmids\": [\"38009729\", \"37258577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the scaffolding and ligase activities are coordinated in cells unresolved\", \"Raf-1 study is single-lab Medium-confidence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened catalytic versatility to non-canonical linkages and additional substrates, showing K48 (NSP8), K27 (CCS), and stabilizing non-K48 ubiquitination (Bcl-2) tied to distinct outcomes.\",\n      \"evidence\": \"Site-specific ubiquitination mutants (NSP8 K97, CCS K76) with domain mapping and functional readouts; ubiquitination microarray and Co-IP for Bcl-2 stabilization\",\n      \"pmids\": [\"38275298\", \"39127340\", \"40552115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting different chain linkages on different substrates unknown\", \"Bcl-2 stabilization mechanism is single-lab Medium-confidence\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated TRIM22 into the RIG-I/MAVS innate signaling axis as a K63-MAVS ubiquitin ligase, and fully delineated its multidomain autophagy-initiation scaffold function.\",\n      \"evidence\": \"K63-specific MAVS ubiquitination with KO/IFN-β reporters and ELF3 promoter ChIP; domain-deletion Co-IP and competitive-binding autophagy-flux assays for ULK1/ATG13/FIP200/Beclin-1 assembly\",\n      \"pmids\": [\"40162781\", \"40337095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial/temporal switch between MAVS amplification and substrate degradation unresolved\", \"Whether scaffold and ligase domains act on overlapping complexes in vivo unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what governs TRIM22's context-dependent choice among catalytic versus scaffold modes, ubiquitin-chain linkage selection, and opposing pro- versus anti-tumorigenic and pro- versus anti-NF-κB outcomes across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking domain architecture to mode selection\", \"Conflicting NF-κB and oncogenic/tumor-suppressive roles not mechanistically reconciled\", \"In vivo physiological substrate hierarchy unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 4, 15, 16, 17, 18, 34]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 15, 17, 18, 34, 48]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 15, 16, 18, 34]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [29, 37]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 13, 36]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 6, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 17, 18, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 20, 33, 36]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [29, 37, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 15, 16, 17, 18, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 29]}\n    ],\n    \"complexes\": [\n      \"ULK1-ATG13-FIP200-ATG101 autophagy initiation complex\",\n      \"class III PI3K (Beclin-1) complex\"\n    ],\n    \"partners\": [\n      \"MAVS\",\n      \"GABARAP\",\n      \"PLEKHM1\",\n      \"Beclin-1\",\n      \"IKKgamma\",\n      \"Raf-1\",\n      \"PHLPP2\",\n      \"ATG13\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}