Affinage

TRIM38

E3 ubiquitin-protein ligase TRIM38 · UniProt O00635

Length
465 aa
Mass
53.4 kDa
Annotated
2026-06-10
29 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM38 (RNF15) is a cytoplasmic RING-domain E3 ubiquitin ligase that acts as a broad negative regulator of innate immune and inflammatory signaling by targeting pathway adaptors and kinases for degradation (PMID:21306652, PMID:26392463). Through site-specific K48-linked polyubiquitination it drives proteasomal degradation of the TLR3/4 adaptor TRIF (at K228), engaging TRIF via its PRYSPRY domain while requiring an intact RING/B-box for catalysis (PMID:23056470, PMID:26392463). The same degradative logic extends to additional signaling nodes: TRIM38 ubiquitinates and degrades TRAF6 to inactivate TAK1-dependent NF-κB and JNK/p38 MAPK signaling (PMID:39033726, PMID:40314083), degrades RIPK1 (PMID:42234342), and downregulates RIG-I by competing with TRIM25 for the RIG-I N-terminus and substituting activating K63 chains with degradative K48 chains as a negative-feedback brake on type I IFN (PMID:38630167). In parallel, TRIM38 mediates lysosome-dependent degradation of TAB2/TAB3 independent of its ligase activity, suppressing TNFα- and IL-1β-triggered NF-κB activation, a route facilitated by the scaffold NLRP6 and operative in osteoclast/osteoblast differentiation (PMID:24434549, PMID:28295271, PMID:29753717). TRIM38 also restrains antiviral and inflammatory programs by degrading MITA/STING and viral proteins such as Zika NS3 (PMID:38012139, PMID:40006954). Beyond immune signaling, TRIM38 functions as a tumor and metabolic regulator: it degrades GLUT1, CCT6A, and p53, and performs non-degradative K63-linked ubiquitination of SQSTM1/p62 (at K420) to impede autophagic flux (PMID:34906161, PMID:40047371, PMID:40059473, PMID:41347593). Its activity is itself tunable by post-translational modification, as the Brucella effector BspF crotonylates TRIM38 at K142 to enhance TRAF6 degradation and dampen host inflammation (PMID:40332097). Hepatocyte-specific studies further establish TRIM38 as an ASK1-degrading suppressor of steatohepatitis (PMID:41260394).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2011 Medium

    Established that TRIM38 is an enzymatically active cytoplasmic E3 ligase, defining the molecular activity that all later substrate work would build on.

    Evidence In vitro ubiquitination assays with RING-domain mutants and immunofluorescence localization

    PMID:21306652

    Open questions at the time
    • No physiological substrate identified in this study
    • Linkage specificity not tied to a biological outcome
  2. 2012 Medium

    Identified the first physiological substrate, showing TRIM38 degrades the TLR3 adaptor TRIF and mapping the PRYSPRY-TRIF interaction, linking the ligase to innate immune attenuation.

    Evidence Co-IP with domain mapping, ubiquitination assays, MG132 rescue in reporter assays

    PMID:23056470

    Open questions at the time
    • Ubiquitin chain topology and exact acceptor site not yet defined
    • In vivo relevance not tested
  3. 2014 High

    Revealed a ligase-independent mode of action, demonstrating TRIM38 routes TAB2/3 to lysosomal degradation to suppress TNFα/IL-1β-driven NF-κB, showing TRIM38 acts through two mechanistically distinct routes.

    Evidence Reciprocal Co-IP, knockout with NF-κB reporters, lysosome-inhibitor rescue and TAB2 translocation assays

    PMID:24434549

    Open questions at the time
    • Adaptor delivering TAB2/3 to the lysosome not identified at this stage
    • How TRIM38 selects lysosomal vs proteasomal routing is unclear
  4. 2015 High

    Pinpointed the K228 acceptor site on TRIF and confirmed dual mechanisms in IFN-primed cells with knockout mice, cementing TRIM38 as an in vivo negative regulator of TLR signaling.

    Evidence Site-specific (K228) ubiquitination assays, proteasome rescue, Trim38 knockout mice challenged with polyI:C/LPS/Salmonella

    PMID:26392463

    Open questions at the time
    • Structural basis of substrate selectivity not resolved
    • Relative contribution of proteasomal vs lysosomal arms in vivo not quantified
  5. 2017 Medium

    Showed that substrate engagement can be scaffold-assisted, with NLRP6 docking TAB2/3 to TRIM38 in synoviocytes, adding a regulatory layer to the lysosomal degradation route.

    Evidence Co-IP demonstrating three-way interaction and NF-κB assays in RA-FLS

    PMID:28295271

    Open questions at the time
    • Direct vs indirect NLRP6-TRIM38 contact not resolved
    • Generality beyond synoviocytes untested
  6. 2018 Medium

    Extended the TAB2 degradation mechanism to bone biology, linking TRIM38-mediated NF-κB suppression to opposing effects on osteoclast and osteoblast differentiation.

    Evidence Gain/loss-of-function in bone precursors with NF-κB reporters and lysosome-dependent degradation assays

    PMID:29753717

    Open questions at the time
    • In vivo skeletal phenotype of TRIM38 manipulation not established here
    • Direct ubiquitination of TAB2 not shown
  7. 2021 Medium

    Broadened the substrate repertoire beyond immunity by identifying GLUT1 as a degradation target, implicating TRIM38 in metabolic and tumor-suppressive control of glycolysis.

    Evidence TAP/MS substrate identification, Co-IP, ubiquitination assay, and bladder cancer xenografts

    PMID:34906161

    Open questions at the time
    • Ubiquitin linkage type and acceptor lysine on GLUT1 not defined
    • Whether glycolysis effect is solely GLUT1-dependent unclear
  8. 2023 Medium

    Added CCT6A and MITA/STING as substrates, connecting TRIM38 to MYC-pathway control in colorectal cancer and to macrophage-polarization-dependent immune tolerance.

    Evidence Co-IP, site-specific ubiquitination (CCT6A K127/K138), AOM/DSS and macrophage polarization/pyroptosis models

    PMID:38012139 PMID:40047371

    Open questions at the time
    • Context-dependence of substrate choice across tissues unresolved
    • Upstream signals directing TRIM38 to each substrate unknown
  9. 2024 Medium

    Defined a feedback mechanism on RIG-I in which TRIM38 competes with TRIM25 for the same N-terminal region and replaces activating K63 with degradative K48 ubiquitination, explaining IFN-I self-limitation.

    Evidence Co-IP with binding-region mapping (aa 25–43), ubiquitination and competition assays in an RSV infection model

    PMID:38630167

    Open questions at the time
    • Stoichiometry of TRIM38/TRIM25 competition not quantified
    • Structural basis of mutually exclusive binding not determined
  10. 2024 Medium

    Directly demonstrated TRAF6 as a K48 ubiquitination substrate driving TAK1/NF-κB inactivation, providing the molecular basis for TRIM38's role in osteoclastogenesis.

    Evidence Co-IP, ubiquitination assay, TRAP/bone resorption assays and OVX mouse model

    PMID:39033726

    Open questions at the time
    • TRAF6 acceptor lysines not mapped
    • Whether earlier TAK1/NF-κB phenotypes act solely via TRAF6 unresolved
  11. 2025 Medium

    Showed TRIM38 activity is itself regulated by a pathogen-driven PTM, with Brucella BspF crotonylating K142 to enhance TRAF6 degradation and suppress host inflammation.

    Evidence Crotonylation proteomics, K142 mutagenesis, ubiquitination assays and cytokine measurements

    PMID:40332097

    Open questions at the time
    • Endogenous (non-pathogen) regulators of TRIM38 crotonylation unknown
    • Structural effect of K142 crotonylation on ligase activity undefined
  12. 2025 High

    Established TRIM38 as a degrader of ASK1 and p53 and a K63-modifier of SQSTM1/p62, expanding its reach to redox/stress signaling, cell-cycle control, and autophagy.

    Evidence Hepatocyte-specific Rnf15 KO with AAV rescue (ASK1), Co-IP/ubiquitination assays (p53, SQSTM1 K420), and tumor/NASH models

    PMID:40059473 PMID:41260394 PMID:41347593

    Open questions at the time
    • How TRIM38 switches between K48-degradative and K63-non-degradative outputs is unresolved
    • Substrate-selection logic across these diverse targets unknown
  13. 2025 Medium

    Extended TRIM38 to viral restriction by degrading Zika NS3 through a lysosome-dependent, RING-dependent route while boosting RIG-I/MDA5-driven IFN-β.

    Evidence Co-IP, RING-deletion mutants, lysosome-inhibitor rescue and KO in U251 cells with IFN-β reporters

    PMID:40006954

    Open questions at the time
    • Mechanism reconciling antiviral RIG-I upregulation with prior RIG-I degradation finding unclear
    • Direct ubiquitination of NS3 not topology-mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single ligase selects among its many substrates and switches between proteasomal K48, non-degradative K63, and ligase-independent lysosomal routing across such diverse tissue contexts.
  • No structural model of substrate recognition
  • No unifying account of linkage/route selection
  • Endogenous physiological inputs that toggle TRIM38 activity largely undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 1
Partners
ASK1RIG-IRIPK1TAB2TAB3TRAF6TRIFTRIM25

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 TRIM38 constitutively interacts with TAB2 and TAB3 and promotes their lysosome-dependent degradation independent of its E3 ubiquitin ligase activity, thereby negatively regulating TNFα- and IL-1β-triggered NF-κB activation Co-immunoprecipitation, overexpression/knockdown/knockout with NF-κB reporter assays, lysosome inhibitor rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 24434549
2015 TRIM38 catalyzes K48-linked polyubiquitination of the TLR3/4 adaptor TRIF at K228 and promotes its proteasomal degradation, negatively regulating TLR3/4-mediated type I IFN and proinflammatory cytokine induction; additionally, TRIM38 induced by type I IFNs mediates lysosomal degradation of TAB2 to suppress TNFα/IL-1β signaling in IFN-primed immune cells Ubiquitination assays with site-specific mutagenesis (K228), proteasome inhibitor rescue, Trim38 knockout mice challenged with polyI:C/LPS/Salmonella Journal of immunology (Baltimore, Md. : 1950) High 26392463
2012 TRIM38 targets the TLR3 adaptor TRIF for K48-linked polyubiquitination and proteasomal degradation; the PRYSPRY domain of TRIM38 interacts with the N-terminus of TRIF, and the RING/B-box domain is required for ubiquitination activity Co-immunoprecipitation, domain mapping, ubiquitination assays, MG132 rescue, overexpression/knockdown reporter assays PloS one Medium 23056470
2011 TRIM38 functions as an E3 ubiquitin ligase, promoting both K48- and K63-linked polyubiquitination of cellular proteins and self-ubiquitination; an intact RING domain is required for these activities; TRIM38 localizes to the cytoplasm; enterovirus 71 infection induces TRIM38 degradation Ubiquitination assays with RING domain mutants, immunofluorescence localization, viral infection experiments Virology journal Medium 21306652
2017 NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, acting as a docking scaffold to promote TAB2/3 lysosomal degradation and suppress NF-κB activation Co-immunoprecipitation, overexpression studies in RA-FLS, NF-κB activity assays FEBS letters Medium 28295271
2018 TRIM38 promotes lysosome-dependent degradation of TAB2 in osteoclast precursor cells, suppressing RANKL-induced NF-κB activation and inhibiting osteoclast differentiation; conversely, TRIM38 promotes osteoblast differentiation via NF-κB suppression Overexpression/knockdown in osteoclast and osteoblast precursors, NF-κB reporter assays, lysosome-dependent degradation assays Bone Medium 29753717
2021 TRIM38 interacts with GLUT1 and promotes its ubiquitination and degradation, thereby restricting glycolytic capacity and tumor progression in bladder cancer cells TAP/MS substrate identification, co-immunoprecipitation, ubiquitination assay, loss-of-function proliferation/migration assays, xenograft model Journal of translational medicine Medium 34906161
2023 TRIM38 binds CCT6A and promotes its K48-linked ubiquitination and degradation at K127/K138 residues; loss of CCT6A degradation elevates c-Myc protein levels and activates the MYC pathway in colorectal cancer Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis, KO/KD functional assays, AOM/DSS tumorigenesis model Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40047371
2023 TRIM38 mediates K48-linked ubiquitination of MITA (STING) promoting its degradation; this ubiquitination is higher in M2 macrophages, keeping MITA expression low and inhibiting pyroptosis, thereby maintaining immune tolerance at the maternal-fetal interface Co-immunoprecipitation, ubiquitination assays, macrophage polarization experiments (M1/M2), functional pyroptosis assays Cell death & disease Medium 38012139
2024 TRIM38, induced by IFN-I during RSV infection, downregulates RIG-I by K48-linked ubiquitination and promotes RIG-I degradation; TRIM38 competes with TRIM25 for binding to the RIG-I N-terminus (aa 25–43 region), preventing TRIM25-mediated K63 ubiquitination and activation of RIG-I, thereby attenuating IFN-I production as a negative feedback mechanism Co-immunoprecipitation with domain mapping, ubiquitination assays, overexpression competition experiments, RSV infection model Inflammation Medium 38630167
2025 TRIM38 interacts with Zika virus NS3 protein via its RING domain and promotes NS3 degradation through a lysosome-dependent mechanism utilizing its E3 ligase activity; RING domain deletion abrogates NS3 interaction and impairs antiviral activity; TRIM38 also upregulates the RIG-I/MDA5 pathway and IFN-β early during ZIKV infection Co-immunoprecipitation, RING domain deletion mutants, lysosome inhibitor rescue, overexpression/knockout in U251 cells, IFN-β reporter assays Viruses Medium 40006954
2022 TRIM38 promotes TRAF6 degradation, leading to inactivation of the TAK1/NF-κB signaling pathway and protection of H9c2 cardiomyoblasts from hypoxia/reoxygenation injury; TAK1 inhibition rescues the H/R injury exacerbated by TRIM38 deficiency Adenoviral overexpression/knockdown, western blotting, TAK1 inhibitor (5Z-7-oxozeaenol) rescue experiments PeerJ Low 36061751
2024 TRIM38 mediates K48-linked polyubiquitination of TRAF6 and promotes its proteasomal degradation in response to RANKL, thereby inhibiting NFATc1 activity and osteoclastogenesis; TRIM38 binds TRAF6 directly Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of TRIM38, TRAP staining, bone resorption assay, OVX mouse model Phytomedicine : international journal of phytotherapy and phytopharmacology Medium 39033726
2025 TRIM38 binds p53 and promotes its ubiquitination-proteasomal degradation; MEHP (a DEHP metabolite) inhibits TRIM38-mediated ubiquitination of p53, leading to p53 accumulation, cell cycle arrest, and impaired trophoblast proliferation Protein binding assay (TRIM38 identified as MEHP target protein), co-immunoprecipitation, ubiquitination assay, transcriptomic/proteomic analysis, cell cycle assays FASEB journal Medium 40059473
2025 TRIM38 promotes K63-linked (non-degradative) ubiquitination of SQSTM1/p62 at K420, which disrupts the interaction between SQSTM1 and LC3 and impedes autophagic flux, thereby suppressing breast cancer progression Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K420), LC3-SQSTM1 interaction assay, in vitro and in vivo tumor models Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 41347593
2025 TRIM38 physically interacts with RIPK1 and promotes its ubiquitination and degradation, thereby suppressing NF-κB pathway activation in the context of diabetic nephropathy Co-immunoprecipitation, ubiquitination assay, overexpression/rescue experiments in HK-2 cells, STZ-induced diabetic mouse model Journal of physiology and biochemistry Low 42234342
2025 TRIM38 interacts with HSPA5 (GRP78) and stabilizes it via K63-dependent ubiquitination, promoting M2 macrophage polarization and suppressing hepatic inflammation in metabolic liver disease Co-immunoprecipitation, ubiquitination assay, macrophage polarization assays, single-cell RNA sequencing, overexpression studies International immunopharmacology Low 40300357
2025 The Brucella effector protein BspF crotonylates TRIM38 at K142, which promotes TRIM38-mediated K48-linked ubiquitination and degradation of TRAF6, thereby inhibiting NF-κB, p38 MAPK, and JNK signaling and reducing pro-inflammatory cytokine secretion to facilitate Brucella intracellular survival Crotonylation proteomics, site-specific mutagenesis (K142), ubiquitination assays, co-immunoprecipitation, cytokine measurement International journal of molecular sciences Medium 40332097
2025 TRIM38 inhibits the TAK1/JNK/P38 MAPK signaling pathway to protect against pressure overload-induced cardiac hypertrophy; Trim38 knockout activates TAK1 and JNK/P38, and dominant-negative TAK1 rescues Trim38 knockdown-induced cardiomyocyte hypertrophy Trim38 knockout mice with TAC model, adenoviral knockdown/overexpression in NRCMs, dominant-negative TAK1 rescue, ubiquitinomics analysis International journal of molecular medicine Medium 40314083
2025 TRIM38 interacts with GRP78 (HSPA5) directly as shown by Co-IP, and upregulation of TRIM38 reduces endoplasmic reticulum stress marker proteins (GRP78, p-PERK, CHOP) to inhibit hepatic stellate cell activation Co-immunoprecipitation, western blotting, TRIM38 knockdown rescue experiments, CCl4 mouse liver fibrosis model Biomedicines Low 42072369
2025 RNF15 (an alias for TRIM38) binds ASK1 and conjugates K48-linked ubiquitination to ASK1, facilitating its degradation and inhibiting ASK1 downstream signaling; hepatocyte-specific Rnf15 ablation promotes steatohepatitis progression Hepatocyte-specific KO mice, lentivirus/AAV-mediated overexpression, co-immunoprecipitation, ubiquitination assay, NASH rodent models Free radical biology & medicine High 41260394

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1261 9288758
2014 TRIM38 inhibits TNFα- and IL-1β-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3. Proceedings of the National Academy of Sciences of the United States of America 125 24434549
2017 Multifaceted roles of TRIM38 in innate immune and inflammatory responses. Cellular & molecular immunology 88 28194022
2015 TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms. Journal of immunology (Baltimore, Md. : 1950) 80 26392463
2012 TRIM38 negatively regulates TLR3-mediated IFN-β signaling by targeting TRIF for degradation. PloS one 67 23056470
2018 TRIM38 regulates NF-κB activation through TAB2 degradation in osteoclast and osteoblast differentiation. Bone 42 29753717
2021 TRIM38 triggers the uniquitination and degradation of glucose transporter type 1 (GLUT1) to restrict tumor progression in bladder cancer. Journal of translational medicine 33 34906161
2017 NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes. FEBS letters 33 28295271
2011 Enterovirus 71 induces degradation of TRIM38, a potential E3 ubiquitin ligase. Virology journal 17 21306652
2021 TRIM38 protects chondrocytes from IL-1β-induced apoptosis and degeneration via negatively modulating nuclear factor (NF)-κB signaling. International immunopharmacology 13 34426118
2023 TRIM38 suppresses migration, invasion, metastasis, and proliferation in non-small cell lung cancer (NSCLC) via regulating the AMPK/NF-κB/NLRP3 pathway. Molecular and cellular biochemistry 12 37566200
2022 TRIM38 protects H9c2 cells from hypoxia/reoxygenation injury via the TRAF6/TAK1/NF-κB signalling pathway. PeerJ 10 36061751
2025 TRIM38 Suppresses the Progression of Colorectal Cancer via Enhancing CCT6A Ubiquitination to Inhibit the MYC Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 8 40047371
2023 Investigation into the role of the MITA-TRIM38 interaction in regulating pyroptosis and maintaining immune tolerance at the maternal-fetal interface. Cell death & disease 8 38012139
2024 TRIM38 Induced in Respiratory Syncytial Virus-infected Cells Downregulates Type I Interferon Expression by Competing with TRIM25 to Bind RIG-I. Inflammation 7 38630167
2000 BSPRY, a novel protein of the Ro-Ret family. Biochimica et biophysica acta 6 10978534
2025 TRIM38 Inhibits Zika Virus by Upregulating RIG-I/MDA5 Pathway and Promoting Ubiquitin-Mediated Degradation of Viral NS3 Protein. Viruses 5 40006954
2025 The Brucella Effector Protein BspF Crotonylates TRIM38 to Inhibit NF-κB and MAPK Signaling Pathway. International journal of molecular sciences 5 40332097
2011 [Identification A novel protein TRIM38 that activate NF-kappaB signaling pathways]. Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology 5 21789858
2025 Di-(2-ethylhexyl)-phthalate disrupts mouse placental growth by regulating the cell cycle of mouse placental trophoblasts through the Trim38-p53 signaling axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 40059473
2025 E3 ubiquitin ligase TRIM38 regulates macrophage polarization to reduce hepatic inflammation by interacting with HSPA5. International immunopharmacology 4 40300357
2025 Trim38 attenuates pressure overload‑induced cardiac hypertrophy by suppressing the TAK1/JNK/P38 signaling pathway. International journal of molecular medicine 3 40314083
2025 Characterization and Functional Analysis of Trim38 in the Immune Response of the Large Yellow Croaker (Larimichthys crocea) Against Pseudomonas plecoglossicida Infection. International journal of molecular sciences 3 40362389
2024 Active fraction of Polyrhachis vicina (Rogers) inhibits osteoclastogenesis by targeting Trim38 mediated proteasomal degradation of TRAF6. Phytomedicine : international journal of phytotherapy and phytopharmacology 3 39033726
2025 Tetrahydromagnolol targets TRIM38 to mediate PANoptosis in cancer cells and has the potential for synergistic cancer therapy. Experimental hematology & oncology 2 41476316
2025 TRIM38 Suppresses Breast Cancer Progression via Modulating SQSTM1 Ubiquitination and Autophagic Flux. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41347593
2026 α-Hederin Alleviates Endoplasmic Reticulum Stress by Upregulating TRIM38 Expression, Thereby Inhibiting Hepatic Stellate Cell Activation and Liver Fibrosis. Biomedicines 0 42072369
2026 TRIM38 alleviates the pathogenesis of diabetic nephropathy by suppressing NF-κB activation via inducing RIPK1 degradation. Journal of physiology and biochemistry 0 42234342
2025 Metabolic insults-initialised nonalcoholic steatohepatitis promoted by fine particulate matter challenge: A mechanism involving RNF15-driven ASK1 degradation. Free radical biology & medicine 0 41260394

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