{"gene":"TRIM7","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2002,"finding":"GNIP2 (isoform encoded by the TRIM7/GNIP gene) physically interacts with glycogenin-1 via its B30.2 domain, confirmed by co-immunoprecipitation, and stimulates glycogenin self-glucosylation 3–4-fold in vitro.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro self-glucosylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay combined with co-IP and Y2H; replicated in follow-up structural study (PMID:14984203)","pmids":["11916970"],"is_preprint":false},{"year":2004,"finding":"The B30.2 domain of GNIP2 is necessary and sufficient for interaction with glycogenin; the coiled-coil domain mediates GNIP2 self-interaction; GNIP1 and GNIP2 also form heterologous complexes.","method":"Yeast two-hybrid deletion analysis, glutaraldehyde crosslinking","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutagenesis with two orthogonal methods (Y2H + crosslinking), single lab","pmids":["14984203"],"is_preprint":false},{"year":2015,"finding":"MSK1, activated downstream of the Ras-Raf-MEK-ERK pathway, directly phosphorylates TRIM7, stimulating its E3 ubiquitin ligase activity. Activated TRIM7 then mediates K63-linked ubiquitination of the AP-1 co-activator RACO-1, stabilizing RACO-1 protein and promoting AP-1-dependent gene expression.","method":"In vitro kinase assay, ubiquitination assay, co-immunoprecipitation, xenograft/transgenic mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including in vitro kinase assay, ubiquitination assay, and in vivo genetic models; single lab with rigorous mechanistic follow-up","pmids":["25851810"],"is_preprint":false},{"year":2019,"finding":"TRIM7 directly interacts with Src kinase and induces K48-linked polyubiquitination of Src, leading to proteasomal degradation of Src and suppression of the Src-mTORC1-S6K1 signaling axis in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, in vivo xenograft models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assay with in vivo validation, single lab","pmids":["31802035"],"is_preprint":false},{"year":2019,"finding":"TRIM7 activates c-Jun/AP-1 signaling in vascular smooth muscle cells, and knockdown of TRIM7 inhibits VSMC proliferation and migration and arrests cells at G1-S phase.","method":"siRNA knockdown, cell cycle analysis, gain- and loss-of-function in apoE-/- atherosclerosis mouse model","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and in vivo model, but mechanism upstream of AP-1 inferred from prior work","pmids":["31625258"],"is_preprint":false},{"year":2020,"finding":"TRIM7 interacts with p65 (NF-κB subunit) via its C-terminal domain (unique from GNIP1 isoform) and promotes K48-linked ubiquitination and proteasomal degradation of p65, suppressing NF-κB signaling in lung cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, in vivo xenograft, truncation mutant analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, truncation analysis, and in vivo model; single lab","pmids":["31958511"],"is_preprint":false},{"year":2020,"finding":"TRIM7 (as RNF90) promotes K48-linked ubiquitination and proteasomal degradation of MITA/STING, negatively regulating DNA virus-triggered innate immune responses; RNF90-deficient mice show increased resistance to DNA virus infection.","method":"Co-immunoprecipitation, ubiquitination assay, RNF90-deficient BMDCs/BMMs/MEFs, in vivo viral challenge","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, multiple cell types, and in vivo knockout mouse model in a single study","pmids":["32126128"],"is_preprint":false},{"year":2020,"finding":"TRIM7 ubiquitinates BRMS1 (breast cancer metastasis suppressor 1), promoting its degradation and thereby facilitating osteosarcoma cell migration and invasion; m6A modification of TRIM7 mRNA by METTL3/YTHDF2 regulates TRIM7 expression.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, RNA immunoprecipitation, PDX mouse model","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, MS, ubiquitination, m6A-RIP), single lab","pmids":["32853985"],"is_preprint":false},{"year":2021,"finding":"TRIM7 is a cell-intrinsic antiviral E3 ubiquitin ligase that restricts multiple human enteroviruses by targeting the viral 2BC membrane remodeling protein for ubiquitination and proteasome-dependent degradation. A single point mutation in viral 2C ATPase confers TRIM7 resistance.","method":"Ubiquitination assay, proteasome inhibitor rescue, in vitro evolution, in vivo mouse infection model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical ubiquitination assay, genetic evolution experiments, and in vivo mouse models; rigorous multi-method study","pmids":["34062120"],"is_preprint":false},{"year":2021,"finding":"TRIM7 (as RNF90) promotes K48-linked ubiquitination and proteasomal degradation of MAVS, negatively regulating RNA virus-triggered innate immune responses independently of STING.","method":"Co-immunoprecipitation, ubiquitination assay, RNF90-deficient cells (HaCaTs, MEFs, BMDMs), in vivo mouse model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, multiple cell types and in vivo model; independent of prior STING finding","pmids":["34512666"],"is_preprint":false},{"year":2021,"finding":"TRIM7 reduces Src protein abundance via the ubiquitin-proteasome pathway in clear cell renal cell carcinoma cells, thereby suppressing HIF-1α accumulation through the Src-PI3K/AKT/mTOR axis and reactive oxygen species production.","method":"siRNA knockdown, ubiquitination assay, PI3K/AKT/mTOR pathway analysis","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, partial mechanistic follow-up","pmids":["34936717"],"is_preprint":false},{"year":2021,"finding":"The B30.2 domain of TRIM7 (crystal structures at 1.6 Å and 1.8 Å) forms a positively charged cavity. Mutational analysis identified Leu423, Ser499, and Cys501 as critical residues for binding glycogenin-1, with the C-terminal 33 amino acids of GN1 required for this interaction.","method":"X-ray crystallography, mutational analysis, molecular dynamics simulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at high resolution combined with mutagenesis; single lab but multiple orthogonal methods","pmids":["33989636"],"is_preprint":false},{"year":2022,"finding":"TRIM7 directly binds and K48-ubiquitinates NCOA4, reducing NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, lentiviral KD/OE, lipid peroxidation and iron assays","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with multiple functional readouts, single lab","pmids":["36067704"],"is_preprint":false},{"year":2022,"finding":"Crystal structures of TRIM7 B30.2 domain in complex with viral 2C peptides reveal that a C-terminal glutamine residue is the primary determinant for TRIM7 substrate recognition. This 'Gln/C-degron' mechanism is shared by norovirus, SARS-CoV-2, and cellular substrates; TRIM7 triggers ubiquitination and degradation of these substrates.","method":"X-ray crystallography, structure-guided mutagenesis, in vitro/cellular ubiquitination and degradation assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with mutagenesis and biochemical/cellular validation; multiple substrate classes tested","pmids":["35982226"],"is_preprint":false},{"year":2022,"finding":"The B30.2 domain of TRIM7 forms a positively charged binding pocket that recognizes a 'U'-shaped Gln/C-degron; the four C-terminal residues of substrates are critical, with the terminal glutamine as the principal determinant. Crystal structures of TRIM7B30.2 with multiple peptides established a Gln/C-degron pathway.","method":"X-ray crystallography, in vitro biochemical assays, cellular degradation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures combined with in vitro and cellular assays; independently corroborates PMID:35982226","pmids":["35867826"],"is_preprint":false},{"year":2022,"finding":"TRIM7's PRYSPRY domain captures substrates with a C-terminal helix terminating in a hydrophobic residue followed by glutamine ('helix-ΦQ' degron). This explains TRIM7's ability to restrict Coxsackievirus and norovirus, as viral 3C protease processing generates C-terminal glutamines on non-structural proteins. Cellular glycogenin also harbors this degron motif.","method":"Biochemical binding assays, viral infection assays, structural inference","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical binding and functional viral restriction data; structural inference without new crystal structures in this paper","pmids":["35893676"],"is_preprint":false},{"year":2022,"finding":"Enterovirus 3C protease (3Cpro) from CVB3 and poliovirus cleaves TRIM7 at glutamine 24 (Q24), generating a truncated TRIM7 with dampened E3 ubiquitin ligase activity and loss of antiviral function.","method":"In vitro cleavage assay, mutagenesis (Q24), ubiquitination assay, viral infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct cleavage site mutagenesis combined with ubiquitination and antiviral functional assays; single lab","pmids":["36106874"],"is_preprint":false},{"year":2022,"finding":"Norovirus NS6 protease (but not the NS6-7 precursor polyprotein) directly binds the substrate-binding domain of Trim7; viruses that escape Trim7 do so by reducing NS6-7 polyprotein cleavage, preventing generation of the Trim7-recognized C-terminal glutamine on NS6.","method":"CRISPR activation screen, in vitro evolution, direct binding assay, viral attenuation analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR screen plus direct binding assay plus in vitro evolution; mechanistic link between polyprotein processing and Trim7 evasion validated by multiple methods","pmids":["35972292"],"is_preprint":false},{"year":2023,"finding":"TRIM7 (as RNF90) promotes K63-linked ubiquitination of ATG7 at lysine 413, positively regulating autophagosome accumulation and autophagy flux; this ubiquitination is required for ATG7's function during starvation, rapamycin stimulation, and L. monocytogenes infection.","method":"Co-immunoprecipitation, ubiquitination assay (site-specific K413 mutation), TRIM7-deficient mice and cells, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific mutagenesis, reciprocal Co-IP, multiple KD/KO/OE systems, and in vivo mouse model","pmids":["36576150"],"is_preprint":false},{"year":2023,"finding":"TRIM7 interacts with MAVS in HEK293T cells (co-localization and co-immunoprecipitation) and positively regulates RIG-I/MDA5/MAVS-mediated IFN-β signaling during EMCV infection, suppressing viral replication.","method":"Co-immunoprecipitation, co-localization, IFN-β promoter reporter assay, siRNA knockdown/overexpression","journal":"Veterinary microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus co-localization, single lab; contrasts with PMID:34512666 showing RNF90/TRIM7 degrades MAVS (opposing roles may reflect context-dependence)","pmids":["37023504"],"is_preprint":false},{"year":2024,"finding":"TRIM7 ubiquitinates SARS-CoV-2 membrane (M) protein at K14, protecting cells from apoptosis; this requires caspase-6 inhibition. Trim7-/- mice show increased apoptosis, viral titers, and pathology. Mutations at M-K14 in circulating variants impair this ubiquitination.","method":"Trim7-/- mouse model, site-specific mutagenesis (K14), recombinant virus (M-K14/K15R), caspase-6 inhibition assay, viral titer measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific mutagenesis, knockout mouse model, recombinant virus, and caspase-6 inhibition experiments; multiple orthogonal methods in single study","pmids":["39616206"],"is_preprint":false},{"year":2024,"finding":"TRIM7 interacts with SLC7A11 via its B30.2/SPRY domain and promotes K48-linked polyubiquitination of SLC7A11, suppressing the SLC7A11/GPX4 axis and inducing ferroptosis in gastric cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, in vivo xenograft, domain mapping","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination assay plus in vivo validation, single lab","pmids":["38509147"],"is_preprint":false},{"year":2024,"finding":"TRIM7 positively regulates Nrf2 stability by reducing K48-linked ubiquitination of Nrf2 (possibly displacing Keap1), thereby activating Nrf2 signaling in HCC cells.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM7 KD/OE cell models, xenograft","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, indirect mechanism (TRIM7 effect on Keap1–Nrf2 interaction inferred, not directly demonstrated)","pmids":["39461200"],"is_preprint":false},{"year":2025,"finding":"TRIM7 directly interacts with HSPA5 via its PRY/SPRY domain (binding to the substrate-binding domain of HSPA5) and promotes K48-linked polyubiquitination and proteasomal degradation of HSPA5, suppressing GPX4 expression and driving ferroptosis in ischemic neurons.","method":"Co-immunoprecipitation, GST pull-down, ubiquitination assay, Trim7 knockout mice, adenoviral KD/OE in neurons","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down plus Co-IP plus ubiquitination assay plus in vivo KO model; single lab","pmids":["41126348"],"is_preprint":false},{"year":2025,"finding":"TRIM7 (as RNF90) acts as an E3 ubiquitin ligase to promote proteasomal degradation of CPT1α (a rate-limiting enzyme in mitochondrial fatty acid oxidation), regulating hepatic lipid metabolism; hepatocyte-specific RNF90 knockout increased CPT1α and enhanced FAO, while E3 ligase-deficient mutant RNF90 had no effect.","method":"Hepatocyte-specific knockout mice, co-immunoprecipitation, ubiquitination assay, E3 ligase-dead mutant, FAO activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO mice, E3-dead mutant rescue, direct ubiquitination assay, and functional FAO readout; multiple orthogonal approaches","pmids":["41651430"],"is_preprint":false},{"year":2025,"finding":"TRIM7 mediates ubiquitin-dependent degradation of the TGEV nucleocapsid (N) protein and also enhances RIG-I-mediated type I interferon signaling to suppress TGEV replication.","method":"Co-immunoprecipitation, ubiquitination assay, RNA-seq with RIG-I signaling modulation, overexpression/knockdown","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay plus RNA-seq pathway analysis; single lab","pmids":["41194212"],"is_preprint":false},{"year":2025,"finding":"TRIM7 competes with P2X7 for binding to the palmitoyl-transferase ZDHHC5, leading to ubiquitination-mediated degradation of ZDHHC5; this disrupts ZDHHC5-dependent palmitoylation of P2X7, preventing P2X7 membrane localization and copper efflux, thereby inducing cuproptosis in synovial macrophages.","method":"Co-immunoprecipitation, fluorescence co-localization, acyl-biotin exchange assay, TRIM7 conditional knockout mice, ICP-MS","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including acyl-biotin exchange, conditional KO, and Co-IP; single lab","pmids":["40768810"],"is_preprint":false},{"year":2025,"finding":"TRIM7 interacts with CMPK2 and negatively regulates CMPK2 expression, suppressing inflammation and apoptosis during renal ischemia-reperfusion injury; TRIM7 knockout exacerbated injury and CMPK2 inhibition reversed injury in TRIM7-KO cells.","method":"Co-immunoprecipitation, TRIM7 KO mice, overexpression, CMPK2 inhibitor rescue","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with functional epistasis, single lab, mechanism of CMPK2 regulation not fully defined at protein level","pmids":["41723894"],"is_preprint":false},{"year":2026,"finding":"TRIM7 depletion in mouse embryos (via morpholino or siRNA) causes developmental arrest at the 8-cell stage by disrupting lysosomal-autophagic pathways; rapamycin-mediated autophagy activation partially rescues embryo development.","method":"Morpholino and siRNA knockdown, scRNA-seq, proteomics, LC3B immunostaining, EU incorporation, rapamycin rescue","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent KD approaches with multi-omic readouts and pharmacological rescue; single lab","pmids":["41845426"],"is_preprint":false},{"year":2026,"finding":"TRIM7 promotes K48-linked ubiquitination and proteasomal degradation of RABV matrix protein (M) at lysine 115, inhibiting rabies virus replication; direct interaction between TRIM7 and RABV-M was demonstrated.","method":"Co-immunoprecipitation, ubiquitination assay (K115 mutagenesis), proteasome inhibitor rescue, overexpression/knockdown, in vivo suckling mouse model","journal":"Emerging microbes & infections","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis plus Co-IP plus ubiquitination assay plus in vivo model; single lab","pmids":["42047619"],"is_preprint":false},{"year":2025,"finding":"NEGATIVE FINDING: Trim7-deficient mice (two independent lines) show no difference in murine norovirus (MNV) burden, tissue distribution, or cytokine responses compared to wild-type mice in both acute and persistent infection models, even when STING and STAT1 pathways are removed.","method":"Two independent Trim7-deficient mouse lines, acute and persistent MNV infection models, viral titer measurement, cytokine analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent knockout mouse lines, multiple infection models, and multiple readouts; robust negative in vivo result","pmids":["40464581"],"is_preprint":false}],"current_model":"TRIM7 is a RING-type E3 ubiquitin ligase whose B30.2/PRYSPRY domain recognizes a 'helix-ΦQ' C-degron (C-terminal glutamine, the Gln/C-degron pathway), enabling it to ubiquitinate and destabilize a broad range of substrates including viral proteins (enterovirus 2BC, SARS-CoV-2 M, RABV-M, TGEV-N), innate immune regulators (STING/MITA via K48-linkage for degradation; MAVS for degradation; ATG7 via K63-linkage for autophagy promotion), and diverse cellular proteins (Src, p65, BRMS1, NCOA4, SLC7A11, HSPA5, CPT1α, ZDHHC5, CMPK2); its activity is stimulated by MSK1-mediated phosphorylation downstream of Ras-ERK signaling, and viral 3C proteases can cleave TRIM7 at Q24 to dampen its ligase activity as an immune evasion mechanism."},"narrative":{"mechanistic_narrative":"TRIM7 is a RING-type E3 ubiquitin ligase that controls protein stability across antiviral defense, innate immune signaling, cell metabolism, and regulated cell death by recognizing substrates through its C-terminal B30.2/PRYSPRY domain [PMID:35982226, PMID:35867826]. Structural and biochemical work established that this domain forms a positively charged pocket that captures a 'U'-shaped C-degron defined by a C-terminal helix terminating in a hydrophobic residue followed by a terminal glutamine (the 'helix-ΦQ'/Gln-C-degron), the principal determinant of substrate selection shared by viral and cellular targets [PMID:35982226, PMID:35867826, PMID:35893676]. The same domain was originally defined as the glycogenin-1 binding module of the GNIP2 isoform, and high-resolution crystal structures mapped the critical contact residues [PMID:11916970, PMID:33989636]. Ligase output is tunable: MSK1 phosphorylates TRIM7 downstream of Ras-ERK signaling to stimulate its activity, and the enzyme switches ubiquitin chain topology to set substrate fate — K48 linkage for proteasomal degradation versus K63 linkage for non-degradative outcomes [PMID:25851810]. As an antiviral effector, TRIM7 ubiquitinates and degrades enterovirus 2BC, SARS-CoV-2 M protein (at K14, blocking caspase-6–dependent apoptosis), and rabies virus M protein (at K115), exploiting C-terminal glutamines generated by viral protease processing; enteroviral 3C protease counters this by cleaving TRIM7 at Q24 to disable it [PMID:34062120, PMID:39616206, PMID:42047619, PMID:36106874, PMID:35972292]. In innate immunity TRIM7/RNF90 drives K48-linked degradation of the signaling adaptors STING/MITA and MAVS to restrain DNA- and RNA-virus–triggered interferon responses [PMID:32126128, PMID:34512666]. Beyond degradation, TRIM7 promotes K63-linked ubiquitination of ATG7 at K413 to support autophagy flux, and TRIM7 loss arrests mouse embryos at the 8-cell stage through disrupted lysosomal-autophagic function [PMID:36576150, PMID:41845426]. It further governs regulated cell death and metabolism by ubiquitinating NCOA4, SLC7A11, and HSPA5 to tune ferroptosis and by degrading CPT1α to limit hepatic fatty-acid oxidation [PMID:36067704, PMID:38509147, PMID:41126348, PMID:41651430].","teleology":[{"year":2002,"claim":"Established the first molecular partner of the TRIM7/GNIP gene product, defining the B30.2 domain as a substrate/partner-recognition module before any ligase role was known.","evidence":"Yeast two-hybrid, co-IP, and in vitro self-glucosylation assay identifying glycogenin-1 binding by GNIP2","pmids":["11916970"],"confidence":"High","gaps":["No ubiquitination or degradation activity tested at this stage","Functional consequence beyond glucosylation stimulation unknown"]},{"year":2004,"claim":"Mapped the domain architecture, showing the B30.2 domain is necessary and sufficient for partner binding while the coiled-coil drives oligomerization.","evidence":"Y2H deletion analysis and glutaraldehyde crosslinking of GNIP isoforms","pmids":["14984203"],"confidence":"Medium","gaps":["Did not connect domains to E3 ligase function","Stoichiometry of oligomers undefined"]},{"year":2015,"claim":"Demonstrated TRIM7 is a regulated E3 ligase whose activity is switched on by upstream kinase signaling, and that chain topology dictates substrate fate.","evidence":"In vitro kinase and ubiquitination assays plus xenograft/transgenic mouse models showing MSK1 phosphorylation and K63 ubiquitination of RACO-1","pmids":["25851810"],"confidence":"High","gaps":["Phosphosite(s) on TRIM7 not fully mapped","Whether topology choice generalizes to other substrates untested here"]},{"year":2019,"claim":"Extended TRIM7 into oncogenic signaling control by showing it directs K48 degradation of Src kinase to suppress downstream growth pathways.","evidence":"Reciprocal Co-IP, ubiquitination assay, and xenograft models in hepatocellular carcinoma","pmids":["31802035"],"confidence":"Medium","gaps":["Degron on Src not defined","Context dependence across tumor types unresolved"]},{"year":2020,"claim":"Defined TRIM7/RNF90 as a negative regulator of antiviral signaling by degrading the adaptors STING/MITA and the NF-κB subunit p65.","evidence":"Co-IP, ubiquitination assays, truncation mapping, and RNF90-deficient cells/mice with viral challenge","pmids":["32126128","31958511"],"confidence":"High","gaps":["Recognition motif on STING/p65 not defined","Relationship to later antiviral (substrate-degrading) roles not reconciled"]},{"year":2021,"claim":"Identified TRIM7 as a cell-intrinsic antiviral ligase targeting viral proteins directly, and showed viruses can escape via single point mutations.","evidence":"Ubiquitination/proteasome rescue assays, in vitro viral evolution, and mouse infection for enterovirus 2BC; plus MAVS degradation in RNF90-deficient cells","pmids":["34062120","34512666"],"confidence":"High","gaps":["At this stage the C-terminal degron rule not yet structurally defined","Apparently opposing pro- vs anti-viral roles unexplained"]},{"year":2022,"claim":"Solved the substrate-recognition code: crystal structures established that TRIM7 reads a C-terminal glutamine 'helix-ΦQ' degron generated by viral protease processing and present on cellular proteins.","evidence":"Multiple X-ray structures of B30.2 with viral and cellular peptides, structure-guided mutagenesis, and degradation assays; plus 3C cleavage at Q24 and norovirus NS6 binding","pmids":["35982226","35867826","35893676","36106874","35972292","33989636"],"confidence":"High","gaps":["How phosphorylation/oligomerization integrate with degron capture unclear","Endogenous substrate repertoire bearing this degron not comprehensively mapped"]},{"year":2022,"claim":"Showed TRIM7 also acts non-degradatively via K63 ubiquitination of ATG7 to promote autophagy, broadening its mechanistic repertoire.","evidence":"Site-specific K413 mutagenesis, reciprocal Co-IP, TRIM7-deficient mice/cells, and autophagy flux assays under starvation and infection","pmids":["36576150"],"confidence":"High","gaps":["Determinant selecting K63 vs K48 output not defined","Whether ATG7 carries the canonical degron untested"]},{"year":2022,"claim":"Connected TRIM7 to regulated cell death by ubiquitinating NCOA4 to limit ferritinophagy and ferroptosis.","evidence":"Co-IP, ubiquitination assay, and iron/lipid-peroxidation readouts in glioblastoma cells","pmids":["36067704"],"confidence":"Medium","gaps":["NCOA4 degron not mapped","Tissue generality unknown"]},{"year":2024,"claim":"Refined the antiviral mechanism in vivo, showing TRIM7 ubiquitinates SARS-CoV-2 M at K14 to block caspase-6–dependent apoptosis and that circulating variants escape this.","evidence":"Trim7-/- mice, site-specific K14 mutagenesis, recombinant virus, and caspase-6 inhibition assays; plus SLC7A11 ubiquitination driving ferroptosis","pmids":["39616206","38509147"],"confidence":"High","gaps":["Interplay between protective (anti-apoptotic) and restrictive antiviral functions unresolved","SLC7A11 (pro-ferroptotic) vs NCOA4 (anti-ferroptotic) roles appear context-divergent"]},{"year":2025,"claim":"Expanded the substrate set into metabolism and additional death pathways, including CPT1α degradation controlling fatty-acid oxidation and HSPA5/ZDHHC5 regulation of ferroptosis and cuproptosis.","evidence":"Conditional/hepatocyte-specific knockout mice, E3-dead mutant rescue, GST pull-down, acyl-biotin exchange, and ubiquitination assays","pmids":["41651430","41126348","40768810"],"confidence":"High","gaps":["Whether these substrates share the Gln/C-degron not all tested","Tissue-specific selectivity mechanism unclear"]},{"year":2025,"claim":"Critically tested TRIM7's antiviral relevance in vivo against norovirus and found no requirement, tempering the generality of the C-degron antiviral model.","evidence":"Two independent Trim7-deficient mouse lines, acute/persistent MNV infection, viral titer and cytokine readouts, including STING/STAT1-null backgrounds","pmids":["40464581"],"confidence":"High","gaps":["Reconciliation with in vitro norovirus restriction data unresolved","Redundancy with other E3 ligases not excluded"]},{"year":null,"claim":"How upstream signals, chain-type selection, and degron capture are integrated to determine which substrates TRIM7 degrades versus stabilizes in a given cell type remains unresolved, as does the discordance between in vitro antiviral activity and in vivo dispensability.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for K48 vs K63 output","Endogenous physiological substrate hierarchy unmapped","In vitro vs in vivo antiviral discordance unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,6,8,13,18,20,24]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,6,8,24]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,6,13,24]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,9,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,14,8,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,20,21,23]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,20,29]}],"complexes":[],"partners":["GYG1","SRC","RELA","STING1","MAVS","ATG7","SLC7A11","HSPA5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C029","full_name":"E3 ubiquitin-protein ligase TRIM7","aliases":["Glycogenin-interacting protein","RING finger protein 90","Tripartite motif-containing protein 7"],"length_aa":511,"mass_kda":56.6,"function":"E3 ubiquitin-protein ligase that have both tumor-promoting and tumor-suppressing activities and functions in several biological processes including innate immunity, regulation of ferroptosis as well as cell proliferation and migration (PubMed:25851810, PubMed:32853985, PubMed:34062120). Acts as an antiviral effector against multiple viruses by targeting specific viral proteins for ubiquitination and degradation including norovirus NTPase protein or SARS-CoV-2 NSP5 and NSP8 proteins (PubMed:34062120, PubMed:35982226). Mechanistically, recognizes the C-terminal glutamine-containing motif usually generated by viral proteases that process the polyproteins and trigger their ubiquitination and subsequent degradation (PubMed:35867826, PubMed:35893676, PubMed:35982226). Mediates 'Lys-63'-linked polyubiquitination and stabilization of the JUN coactivator RNF187 in response to growth factor signaling via the MEK/ERK pathway, thereby regulating JUN transactivation and cellular proliferation (PubMed:25851810). Promotes the TLR4-mediated signaling activation through its E3 ligase domain leading to production of pro-inflammatory cytokines and type I interferon (By similarity). Also plays a negative role in the regulation of exogenous cytosolic DNA virus-triggered immune response. Mechanistically, enhances the 'Lys-48'-linked ubiquitination of STING1 leading to its proteasome-dependent degradation (PubMed:32126128). Mediates the ubiquitination of the SIN3-HDAC chromatin remodeling complex component BRMS1 (PubMed:32853985). Modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells by ubiquitinating NCOA4, leading to its degradation (PubMed:36067704) (Microbial infection) Promotes Zika virus replication by mediating envelope protein E ubiquitination","subcellular_location":"Nucleus; Cytoplasm; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q9C029/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM7","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM7","total_profiled":1310},"omim":[{"mim_id":"609315","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 7; TRIM7","url":"https://www.omim.org/entry/609315"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":52.4},{"tissue":"skeletal muscle","ntpm":181.0},{"tissue":"tongue","ntpm":47.8}],"url":"https://www.proteinatlas.org/search/TRIM7"},"hgnc":{"alias_symbol":["RNF90","GNIP"],"prev_symbol":[]},"alphafold":{"accession":"Q9C029","domains":[{"cath_id":"3.30.40.10","chopping":"25-57_74-93","consensus_level":"medium","plddt":90.6628,"start":25,"end":93},{"cath_id":"-","chopping":"231-338","consensus_level":"medium","plddt":89.4163,"start":231,"end":338},{"cath_id":"2.60.120.920","chopping":"356-511","consensus_level":"high","plddt":92.7867,"start":356,"end":511}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C029","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C029-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C029-F1-predicted_aligned_error_v6.png","plddt_mean":85.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM7","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM7"},"sequence":{"accession":"Q9C029","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C029.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C029/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C029"}},"corpus_meta":[{"pmid":"36067704","id":"PMC_36067704","title":"TRIM7 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\"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay combined with co-IP and Y2H; replicated in follow-up structural study (PMID:14984203)\",\n      \"pmids\": [\"11916970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The B30.2 domain of GNIP2 is necessary and sufficient for interaction with glycogenin; the coiled-coil domain mediates GNIP2 self-interaction; GNIP1 and GNIP2 also form heterologous complexes.\",\n      \"method\": \"Yeast two-hybrid deletion analysis, glutaraldehyde crosslinking\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutagenesis with two orthogonal methods (Y2H + crosslinking), single lab\",\n      \"pmids\": [\"14984203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MSK1, activated downstream of the Ras-Raf-MEK-ERK pathway, directly phosphorylates TRIM7, stimulating its E3 ubiquitin ligase activity. Activated TRIM7 then mediates K63-linked ubiquitination of the AP-1 co-activator RACO-1, stabilizing RACO-1 protein and promoting AP-1-dependent gene expression.\",\n      \"method\": \"In vitro kinase assay, ubiquitination assay, co-immunoprecipitation, xenograft/transgenic mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including in vitro kinase assay, ubiquitination assay, and in vivo genetic models; single lab with rigorous mechanistic follow-up\",\n      \"pmids\": [\"25851810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM7 directly interacts with Src kinase and induces K48-linked polyubiquitination of Src, leading to proteasomal degradation of Src and suppression of the Src-mTORC1-S6K1 signaling axis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, in vivo xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assay with in vivo validation, single lab\",\n      \"pmids\": [\"31802035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM7 activates c-Jun/AP-1 signaling in vascular smooth muscle cells, and knockdown of TRIM7 inhibits VSMC proliferation and migration and arrests cells at G1-S phase.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, gain- and loss-of-function in apoE-/- atherosclerosis mouse model\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and in vivo model, but mechanism upstream of AP-1 inferred from prior work\",\n      \"pmids\": [\"31625258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM7 interacts with p65 (NF-κB subunit) via its C-terminal domain (unique from GNIP1 isoform) and promotes K48-linked ubiquitination and proteasomal degradation of p65, suppressing NF-κB signaling in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, in vivo xenograft, truncation mutant analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, truncation analysis, and in vivo model; single lab\",\n      \"pmids\": [\"31958511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM7 (as RNF90) promotes K48-linked ubiquitination and proteasomal degradation of MITA/STING, negatively regulating DNA virus-triggered innate immune responses; RNF90-deficient mice show increased resistance to DNA virus infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RNF90-deficient BMDCs/BMMs/MEFs, in vivo viral challenge\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, multiple cell types, and in vivo knockout mouse model in a single study\",\n      \"pmids\": [\"32126128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM7 ubiquitinates BRMS1 (breast cancer metastasis suppressor 1), promoting its degradation and thereby facilitating osteosarcoma cell migration and invasion; m6A modification of TRIM7 mRNA by METTL3/YTHDF2 regulates TRIM7 expression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, RNA immunoprecipitation, PDX mouse model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, MS, ubiquitination, m6A-RIP), single lab\",\n      \"pmids\": [\"32853985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM7 is a cell-intrinsic antiviral E3 ubiquitin ligase that restricts multiple human enteroviruses by targeting the viral 2BC membrane remodeling protein for ubiquitination and proteasome-dependent degradation. A single point mutation in viral 2C ATPase confers TRIM7 resistance.\",\n      \"method\": \"Ubiquitination assay, proteasome inhibitor rescue, in vitro evolution, in vivo mouse infection model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical ubiquitination assay, genetic evolution experiments, and in vivo mouse models; rigorous multi-method study\",\n      \"pmids\": [\"34062120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM7 (as RNF90) promotes K48-linked ubiquitination and proteasomal degradation of MAVS, negatively regulating RNA virus-triggered innate immune responses independently of STING.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RNF90-deficient cells (HaCaTs, MEFs, BMDMs), in vivo mouse model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, multiple cell types and in vivo model; independent of prior STING finding\",\n      \"pmids\": [\"34512666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM7 reduces Src protein abundance via the ubiquitin-proteasome pathway in clear cell renal cell carcinoma cells, thereby suppressing HIF-1α accumulation through the Src-PI3K/AKT/mTOR axis and reactive oxygen species production.\",\n      \"method\": \"siRNA knockdown, ubiquitination assay, PI3K/AKT/mTOR pathway analysis\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"34936717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The B30.2 domain of TRIM7 (crystal structures at 1.6 Å and 1.8 Å) forms a positively charged cavity. Mutational analysis identified Leu423, Ser499, and Cys501 as critical residues for binding glycogenin-1, with the C-terminal 33 amino acids of GN1 required for this interaction.\",\n      \"method\": \"X-ray crystallography, mutational analysis, molecular dynamics simulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at high resolution combined with mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33989636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM7 directly binds and K48-ubiquitinates NCOA4, reducing NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, lentiviral KD/OE, lipid peroxidation and iron assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with multiple functional readouts, single lab\",\n      \"pmids\": [\"36067704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structures of TRIM7 B30.2 domain in complex with viral 2C peptides reveal that a C-terminal glutamine residue is the primary determinant for TRIM7 substrate recognition. This 'Gln/C-degron' mechanism is shared by norovirus, SARS-CoV-2, and cellular substrates; TRIM7 triggers ubiquitination and degradation of these substrates.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, in vitro/cellular ubiquitination and degradation assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with mutagenesis and biochemical/cellular validation; multiple substrate classes tested\",\n      \"pmids\": [\"35982226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The B30.2 domain of TRIM7 forms a positively charged binding pocket that recognizes a 'U'-shaped Gln/C-degron; the four C-terminal residues of substrates are critical, with the terminal glutamine as the principal determinant. Crystal structures of TRIM7B30.2 with multiple peptides established a Gln/C-degron pathway.\",\n      \"method\": \"X-ray crystallography, in vitro biochemical assays, cellular degradation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures combined with in vitro and cellular assays; independently corroborates PMID:35982226\",\n      \"pmids\": [\"35867826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM7's PRYSPRY domain captures substrates with a C-terminal helix terminating in a hydrophobic residue followed by glutamine ('helix-ΦQ' degron). This explains TRIM7's ability to restrict Coxsackievirus and norovirus, as viral 3C protease processing generates C-terminal glutamines on non-structural proteins. Cellular glycogenin also harbors this degron motif.\",\n      \"method\": \"Biochemical binding assays, viral infection assays, structural inference\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding and functional viral restriction data; structural inference without new crystal structures in this paper\",\n      \"pmids\": [\"35893676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Enterovirus 3C protease (3Cpro) from CVB3 and poliovirus cleaves TRIM7 at glutamine 24 (Q24), generating a truncated TRIM7 with dampened E3 ubiquitin ligase activity and loss of antiviral function.\",\n      \"method\": \"In vitro cleavage assay, mutagenesis (Q24), ubiquitination assay, viral infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct cleavage site mutagenesis combined with ubiquitination and antiviral functional assays; single lab\",\n      \"pmids\": [\"36106874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Norovirus NS6 protease (but not the NS6-7 precursor polyprotein) directly binds the substrate-binding domain of Trim7; viruses that escape Trim7 do so by reducing NS6-7 polyprotein cleavage, preventing generation of the Trim7-recognized C-terminal glutamine on NS6.\",\n      \"method\": \"CRISPR activation screen, in vitro evolution, direct binding assay, viral attenuation analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR screen plus direct binding assay plus in vitro evolution; mechanistic link between polyprotein processing and Trim7 evasion validated by multiple methods\",\n      \"pmids\": [\"35972292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM7 (as RNF90) promotes K63-linked ubiquitination of ATG7 at lysine 413, positively regulating autophagosome accumulation and autophagy flux; this ubiquitination is required for ATG7's function during starvation, rapamycin stimulation, and L. monocytogenes infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (site-specific K413 mutation), TRIM7-deficient mice and cells, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific mutagenesis, reciprocal Co-IP, multiple KD/KO/OE systems, and in vivo mouse model\",\n      \"pmids\": [\"36576150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM7 interacts with MAVS in HEK293T cells (co-localization and co-immunoprecipitation) and positively regulates RIG-I/MDA5/MAVS-mediated IFN-β signaling during EMCV infection, suppressing viral replication.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, IFN-β promoter reporter assay, siRNA knockdown/overexpression\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus co-localization, single lab; contrasts with PMID:34512666 showing RNF90/TRIM7 degrades MAVS (opposing roles may reflect context-dependence)\",\n      \"pmids\": [\"37023504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM7 ubiquitinates SARS-CoV-2 membrane (M) protein at K14, protecting cells from apoptosis; this requires caspase-6 inhibition. Trim7-/- mice show increased apoptosis, viral titers, and pathology. Mutations at M-K14 in circulating variants impair this ubiquitination.\",\n      \"method\": \"Trim7-/- mouse model, site-specific mutagenesis (K14), recombinant virus (M-K14/K15R), caspase-6 inhibition assay, viral titer measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific mutagenesis, knockout mouse model, recombinant virus, and caspase-6 inhibition experiments; multiple orthogonal methods in single study\",\n      \"pmids\": [\"39616206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM7 interacts with SLC7A11 via its B30.2/SPRY domain and promotes K48-linked polyubiquitination of SLC7A11, suppressing the SLC7A11/GPX4 axis and inducing ferroptosis in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, in vivo xenograft, domain mapping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination assay plus in vivo validation, single lab\",\n      \"pmids\": [\"38509147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM7 positively regulates Nrf2 stability by reducing K48-linked ubiquitination of Nrf2 (possibly displacing Keap1), thereby activating Nrf2 signaling in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM7 KD/OE cell models, xenograft\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, indirect mechanism (TRIM7 effect on Keap1–Nrf2 interaction inferred, not directly demonstrated)\",\n      \"pmids\": [\"39461200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM7 directly interacts with HSPA5 via its PRY/SPRY domain (binding to the substrate-binding domain of HSPA5) and promotes K48-linked polyubiquitination and proteasomal degradation of HSPA5, suppressing GPX4 expression and driving ferroptosis in ischemic neurons.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, ubiquitination assay, Trim7 knockout mice, adenoviral KD/OE in neurons\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down plus Co-IP plus ubiquitination assay plus in vivo KO model; single lab\",\n      \"pmids\": [\"41126348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM7 (as RNF90) acts as an E3 ubiquitin ligase to promote proteasomal degradation of CPT1α (a rate-limiting enzyme in mitochondrial fatty acid oxidation), regulating hepatic lipid metabolism; hepatocyte-specific RNF90 knockout increased CPT1α and enhanced FAO, while E3 ligase-deficient mutant RNF90 had no effect.\",\n      \"method\": \"Hepatocyte-specific knockout mice, co-immunoprecipitation, ubiquitination assay, E3 ligase-dead mutant, FAO activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO mice, E3-dead mutant rescue, direct ubiquitination assay, and functional FAO readout; multiple orthogonal approaches\",\n      \"pmids\": [\"41651430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM7 mediates ubiquitin-dependent degradation of the TGEV nucleocapsid (N) protein and also enhances RIG-I-mediated type I interferon signaling to suppress TGEV replication.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RNA-seq with RIG-I signaling modulation, overexpression/knockdown\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay plus RNA-seq pathway analysis; single lab\",\n      \"pmids\": [\"41194212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM7 competes with P2X7 for binding to the palmitoyl-transferase ZDHHC5, leading to ubiquitination-mediated degradation of ZDHHC5; this disrupts ZDHHC5-dependent palmitoylation of P2X7, preventing P2X7 membrane localization and copper efflux, thereby inducing cuproptosis in synovial macrophages.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence co-localization, acyl-biotin exchange assay, TRIM7 conditional knockout mice, ICP-MS\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including acyl-biotin exchange, conditional KO, and Co-IP; single lab\",\n      \"pmids\": [\"40768810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM7 interacts with CMPK2 and negatively regulates CMPK2 expression, suppressing inflammation and apoptosis during renal ischemia-reperfusion injury; TRIM7 knockout exacerbated injury and CMPK2 inhibition reversed injury in TRIM7-KO cells.\",\n      \"method\": \"Co-immunoprecipitation, TRIM7 KO mice, overexpression, CMPK2 inhibitor rescue\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with functional epistasis, single lab, mechanism of CMPK2 regulation not fully defined at protein level\",\n      \"pmids\": [\"41723894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM7 depletion in mouse embryos (via morpholino or siRNA) causes developmental arrest at the 8-cell stage by disrupting lysosomal-autophagic pathways; rapamycin-mediated autophagy activation partially rescues embryo development.\",\n      \"method\": \"Morpholino and siRNA knockdown, scRNA-seq, proteomics, LC3B immunostaining, EU incorporation, rapamycin rescue\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent KD approaches with multi-omic readouts and pharmacological rescue; single lab\",\n      \"pmids\": [\"41845426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM7 promotes K48-linked ubiquitination and proteasomal degradation of RABV matrix protein (M) at lysine 115, inhibiting rabies virus replication; direct interaction between TRIM7 and RABV-M was demonstrated.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K115 mutagenesis), proteasome inhibitor rescue, overexpression/knockdown, in vivo suckling mouse model\",\n      \"journal\": \"Emerging microbes & infections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis plus Co-IP plus ubiquitination assay plus in vivo model; single lab\",\n      \"pmids\": [\"42047619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NEGATIVE FINDING: Trim7-deficient mice (two independent lines) show no difference in murine norovirus (MNV) burden, tissue distribution, or cytokine responses compared to wild-type mice in both acute and persistent infection models, even when STING and STAT1 pathways are removed.\",\n      \"method\": \"Two independent Trim7-deficient mouse lines, acute and persistent MNV infection models, viral titer measurement, cytokine analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent knockout mouse lines, multiple infection models, and multiple readouts; robust negative in vivo result\",\n      \"pmids\": [\"40464581\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM7 is a RING-type E3 ubiquitin ligase whose B30.2/PRYSPRY domain recognizes a 'helix-ΦQ' C-degron (C-terminal glutamine, the Gln/C-degron pathway), enabling it to ubiquitinate and destabilize a broad range of substrates including viral proteins (enterovirus 2BC, SARS-CoV-2 M, RABV-M, TGEV-N), innate immune regulators (STING/MITA via K48-linkage for degradation; MAVS for degradation; ATG7 via K63-linkage for autophagy promotion), and diverse cellular proteins (Src, p65, BRMS1, NCOA4, SLC7A11, HSPA5, CPT1α, ZDHHC5, CMPK2); its activity is stimulated by MSK1-mediated phosphorylation downstream of Ras-ERK signaling, and viral 3C proteases can cleave TRIM7 at Q24 to dampen its ligase activity as an immune evasion mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM7 is a RING-type E3 ubiquitin ligase that controls protein stability across antiviral defense, innate immune signaling, cell metabolism, and regulated cell death by recognizing substrates through its C-terminal B30.2/PRYSPRY domain [#13, #14]. Structural and biochemical work established that this domain forms a positively charged pocket that captures a 'U'-shaped C-degron defined by a C-terminal helix terminating in a hydrophobic residue followed by a terminal glutamine (the 'helix-\\u03a6Q'/Gln-C-degron), the principal determinant of substrate selection shared by viral and cellular targets [#13, #14, #15]. The same domain was originally defined as the glycogenin-1 binding module of the GNIP2 isoform, and high-resolution crystal structures mapped the critical contact residues [#0, #11]. Ligase output is tunable: MSK1 phosphorylates TRIM7 downstream of Ras-ERK signaling to stimulate its activity, and the enzyme switches ubiquitin chain topology to set substrate fate \\u2014 K48 linkage for proteasomal degradation versus K63 linkage for non-degradative outcomes [#2]. As an antiviral effector, TRIM7 ubiquitinates and degrades enterovirus 2BC, SARS-CoV-2 M protein (at K14, blocking caspase-6\\u2013dependent apoptosis), and rabies virus M protein (at K115), exploiting C-terminal glutamines generated by viral protease processing; enteroviral 3C protease counters this by cleaving TRIM7 at Q24 to disable it [#8, #20, #29, #16, #17]. In innate immunity TRIM7/RNF90 drives K48-linked degradation of the signaling adaptors STING/MITA and MAVS to restrain DNA- and RNA-virus\\u2013triggered interferon responses [#6, #9]. Beyond degradation, TRIM7 promotes K63-linked ubiquitination of ATG7 at K413 to support autophagy flux, and TRIM7 loss arrests mouse embryos at the 8-cell stage through disrupted lysosomal-autophagic function [#18, #28]. It further governs regulated cell death and metabolism by ubiquitinating NCOA4, SLC7A11, and HSPA5 to tune ferroptosis and by degrading CPT1\\u03b1 to limit hepatic fatty-acid oxidation [#12, #21, #23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first molecular partner of the TRIM7/GNIP gene product, defining the B30.2 domain as a substrate/partner-recognition module before any ligase role was known.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and in vitro self-glucosylation assay identifying glycogenin-1 binding by GNIP2\",\n      \"pmids\": [\"11916970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ubiquitination or degradation activity tested at this stage\", \"Functional consequence beyond glucosylation stimulation unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the domain architecture, showing the B30.2 domain is necessary and sufficient for partner binding while the coiled-coil drives oligomerization.\",\n      \"evidence\": \"Y2H deletion analysis and glutaraldehyde crosslinking of GNIP isoforms\",\n      \"pmids\": [\"14984203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect domains to E3 ligase function\", \"Stoichiometry of oligomers undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated TRIM7 is a regulated E3 ligase whose activity is switched on by upstream kinase signaling, and that chain topology dictates substrate fate.\",\n      \"evidence\": \"In vitro kinase and ubiquitination assays plus xenograft/transgenic mouse models showing MSK1 phosphorylation and K63 ubiquitination of RACO-1\",\n      \"pmids\": [\"25851810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite(s) on TRIM7 not fully mapped\", \"Whether topology choice generalizes to other substrates untested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TRIM7 into oncogenic signaling control by showing it directs K48 degradation of Src kinase to suppress downstream growth pathways.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, and xenograft models in hepatocellular carcinoma\",\n      \"pmids\": [\"31802035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron on Src not defined\", \"Context dependence across tumor types unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined TRIM7/RNF90 as a negative regulator of antiviral signaling by degrading the adaptors STING/MITA and the NF-\\u03baB subunit p65.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, truncation mapping, and RNF90-deficient cells/mice with viral challenge\",\n      \"pmids\": [\"32126128\", \"31958511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recognition motif on STING/p65 not defined\", \"Relationship to later antiviral (substrate-degrading) roles not reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified TRIM7 as a cell-intrinsic antiviral ligase targeting viral proteins directly, and showed viruses can escape via single point mutations.\",\n      \"evidence\": \"Ubiquitination/proteasome rescue assays, in vitro viral evolution, and mouse infection for enterovirus 2BC; plus MAVS degradation in RNF90-deficient cells\",\n      \"pmids\": [\"34062120\", \"34512666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"At this stage the C-terminal degron rule not yet structurally defined\", \"Apparently opposing pro- vs anti-viral roles unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Solved the substrate-recognition code: crystal structures established that TRIM7 reads a C-terminal glutamine 'helix-\\u03a6Q' degron generated by viral protease processing and present on cellular proteins.\",\n      \"evidence\": \"Multiple X-ray structures of B30.2 with viral and cellular peptides, structure-guided mutagenesis, and degradation assays; plus 3C cleavage at Q24 and norovirus NS6 binding\",\n      \"pmids\": [\"35982226\", \"35867826\", \"35893676\", \"36106874\", \"35972292\", \"33989636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation/oligomerization integrate with degron capture unclear\", \"Endogenous substrate repertoire bearing this degron not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed TRIM7 also acts non-degradatively via K63 ubiquitination of ATG7 to promote autophagy, broadening its mechanistic repertoire.\",\n      \"evidence\": \"Site-specific K413 mutagenesis, reciprocal Co-IP, TRIM7-deficient mice/cells, and autophagy flux assays under starvation and infection\",\n      \"pmids\": [\"36576150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinant selecting K63 vs K48 output not defined\", \"Whether ATG7 carries the canonical degron untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected TRIM7 to regulated cell death by ubiquitinating NCOA4 to limit ferritinophagy and ferroptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and iron/lipid-peroxidation readouts in glioblastoma cells\",\n      \"pmids\": [\"36067704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NCOA4 degron not mapped\", \"Tissue generality unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the antiviral mechanism in vivo, showing TRIM7 ubiquitinates SARS-CoV-2 M at K14 to block caspase-6\\u2013dependent apoptosis and that circulating variants escape this.\",\n      \"evidence\": \"Trim7-/- mice, site-specific K14 mutagenesis, recombinant virus, and caspase-6 inhibition assays; plus SLC7A11 ubiquitination driving ferroptosis\",\n      \"pmids\": [\"39616206\", \"38509147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between protective (anti-apoptotic) and restrictive antiviral functions unresolved\", \"SLC7A11 (pro-ferroptotic) vs NCOA4 (anti-ferroptotic) roles appear context-divergent\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the substrate set into metabolism and additional death pathways, including CPT1\\u03b1 degradation controlling fatty-acid oxidation and HSPA5/ZDHHC5 regulation of ferroptosis and cuproptosis.\",\n      \"evidence\": \"Conditional/hepatocyte-specific knockout mice, E3-dead mutant rescue, GST pull-down, acyl-biotin exchange, and ubiquitination assays\",\n      \"pmids\": [\"41651430\", \"41126348\", \"40768810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these substrates share the Gln/C-degron not all tested\", \"Tissue-specific selectivity mechanism unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Critically tested TRIM7's antiviral relevance in vivo against norovirus and found no requirement, tempering the generality of the C-degron antiviral model.\",\n      \"evidence\": \"Two independent Trim7-deficient mouse lines, acute/persistent MNV infection, viral titer and cytokine readouts, including STING/STAT1-null backgrounds\",\n      \"pmids\": [\"40464581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with in vitro norovirus restriction data unresolved\", \"Redundancy with other E3 ligases not excluded\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream signals, chain-type selection, and degron capture are integrated to determine which substrates TRIM7 degrades versus stabilizes in a given cell type remains unresolved, as does the discordance between in vitro antiviral activity and in vivo dispensability.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for K48 vs K63 output\", \"Endogenous physiological substrate hierarchy unmapped\", \"In vitro vs in vivo antiviral discordance unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0061630\", \"supporting_discovery_ids\": [2, 6, 8, 13, 18, 24]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 6, 8, 13, 18, 20, 24]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 6, 8, 24]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 6, 13, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 9, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 14, 8, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 20, 21, 23]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 20, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GYG1\", \"SRC\", \"RELA\", \"STING1\", \"MAVS\", \"ATG7\", \"SLC7A11\", \"HSPA5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}