Affinage

TRIM38

E3 ubiquitin-protein ligase TRIM38 · UniProt O00635

Length
465 aa
Mass
53.4 kDa
Annotated
2026-04-28
27 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM38 is a RING-domain E3 ubiquitin ligase that serves as a broad negative regulator of innate immune, inflammatory, and proliferative signaling by targeting multiple pathway adaptors for degradation. It catalyzes K48-linked polyubiquitination and proteasomal degradation of TRIF, RIG-I, TRAF6, MITA/STING, CCT6A, GLUT1, and p53, while independently promoting lysosome-dependent degradation of TAB2/TAB3 through a mechanism that does not require its ligase activity (PMID:24434549, PMID:26392463, PMID:23056470, PMID:38630167, PMID:39033726, PMID:38012139, PMID:40047371, PMID:34906161, PMID:40059473). TRIM38 also catalyzes K63-linked ubiquitination that stabilizes HSPA5 to promote M2 macrophage polarization and modifies SQSTM1/p62 at K420 to impede autophagic flux (PMID:40300357, PMID:41347593). Through these activities, TRIM38 restrains TLR3/4-, TNFα/IL-1β-, and cytosolic nucleic acid sensor-mediated signaling, limits NF-κB and MAPK activation in diverse contexts including osteoclastogenesis and cardiac hypertrophy, and restricts Zika virus replication via lysosomal degradation of the NS3 protein (PMID:29753717, PMID:40314083, PMID:40006954).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2011 Medium

    Establishing that TRIM38 possesses intrinsic E3 ubiquitin ligase activity dependent on its RING domain answered the foundational question of whether this TRIM family member is an active enzyme capable of conjugating both K48- and K63-linked ubiquitin chains.

    Evidence In vitro and cellular ubiquitination assays with RING domain mutagenesis

    PMID:21306652

    Open questions at the time
    • No endogenous substrates identified at this stage
    • Self-ubiquitination function unclear
    • No in vivo confirmation
  2. 2012 Medium

    Identification of TRIF as a direct K48-linked ubiquitination substrate of TRIM38 established the first mechanistic link between TRIM38 and innate immune signaling, showing it negatively regulates TLR3 signaling by degrading a key adaptor.

    Evidence Co-IP, domain mapping (PRYSPRY–TRIF N-terminus), K48 ubiquitination assays, proteasome inhibition in overexpression/knockdown systems

    PMID:23056470

    Open questions at the time
    • Single lab, no in vivo validation at this point
    • Specific ubiquitination site on TRIF not mapped
  3. 2014 High

    Discovery that TRIM38 promotes lysosomal degradation of TAB2/TAB3 independently of its E3 ligase activity revealed a second, non-canonical degradation mechanism by which TRIM38 suppresses TNFα/IL-1β-triggered NF-κB activation.

    Evidence Reciprocal Co-IP, KO cells, lysosome inhibitor rescue, NF-κB reporter assays

    PMID:24434549

    Open questions at the time
    • Mechanism of lysosome targeting without ubiquitination unresolved
    • No structural basis for TAB2/3 recognition
  4. 2015 High

    In vivo validation using Trim38 knockout mice confirmed TRIM38 as a physiological negative regulator of TLR3/4 signaling (via TRIF K228 ubiquitination) and TNFα/IL-1β signaling (via IFN-induced TAB2 degradation), establishing a type I IFN-driven feedback loop.

    Evidence Trim38 KO mice challenged with LPS, poly(I:C), and Salmonella; K48 ubiquitination at K228; IFN priming experiments

    PMID:26392463

    Open questions at the time
    • Relative contribution of TRIF vs TAB2 arms in vivo not dissected
    • Upstream regulation of TRIM38 expression beyond IFN incompletely characterized
  5. 2017 Medium

    Showing that NLRP6 acts as a scaffold to facilitate TRIM38–TAB2/3 interaction in rheumatoid arthritis synoviocytes revealed how TRIM38 activity can be modulated by accessory proteins in disease-specific contexts.

    Evidence Co-IP and overexpression in RA fibroblast-like synoviocytes with cytokine readouts

    PMID:28295271

    Open questions at the time
    • Single lab, not replicated in other cell types
    • Direct vs indirect scaffolding not biochemically resolved
  6. 2018 Medium

    Extension of the TAB2 degradation mechanism to osteoclast biology demonstrated TRIM38 inhibits RANKL-induced osteoclastogenesis and promotes osteoblast differentiation via NF-κB suppression, broadening TRIM38's physiological scope beyond innate immunity.

    Evidence Overexpression/knockdown in osteoclast/osteoblast precursors, NF-κB reporters, differentiation markers

    PMID:29753717

    Open questions at the time
    • No in vivo bone phenotype reported
    • Contribution relative to other TRIM E3s in bone homeostasis unknown
  7. 2021 Medium

    Identification of GLUT1 as a TRIM38 ubiquitination substrate linked TRIM38 to metabolic regulation, showing it suppresses glycolysis and tumor growth in bladder cancer by degrading the glucose transporter.

    Evidence TAP/MS substrate discovery, Co-IP, ubiquitination assay, xenograft models

    PMID:34906161

    Open questions at the time
    • Ubiquitin linkage type and site on GLUT1 not specified
    • Mechanism of TRIM38 downregulation in tumors not defined
  8. 2022 Medium

    Demonstration that TRIM38 degrades TRAF6 to inactivate the TAK1/NF-κB axis in cardiomyocytes, with TAK1 inhibitor rescuing TRIM38-deficiency phenotypes, established TRIM38 as cardioprotective during ischemia-reperfusion injury.

    Evidence Adenoviral OE/KD in H9c2 cells under hypoxia/reoxygenation, TAK1 inhibitor epistasis

    PMID:36061751

    Open questions at the time
    • In vitro H/R model only; no in vivo cardiac ischemia model at this stage
    • Ubiquitin linkage on TRAF6 not confirmed here
  9. 2023 Medium

    Showing TRIM38 K48-ubiquitinates MITA/STING in M2 macrophages to inhibit pyroptosis at the maternal-fetal interface expanded the substrate repertoire to the cGAS-STING pathway and revealed cell-type-specific regulation of TRIM38 activity.

    Evidence Co-IP, K48 ubiquitination assays, macrophage polarization, pyroptosis assays

    PMID:38012139

    Open questions at the time
    • Mechanism governing differential TRIM38 activity in M1 vs M2 not elucidated
    • No in vivo pregnancy model
  10. 2024 Medium

    Discovery that TRIM38 competes with TRIM25 for overlapping RIG-I binding sites, promoting K48 degradation of RIG-I instead of K63 activation, defined a direct antagonistic regulatory circuit controlling IFN-I production via the same sensor.

    Evidence Co-IP, domain mapping of RIG-I aa 25–43, K48/K63 ubiquitination assays, IFN-β reporters

    PMID:38630167

    Open questions at the time
    • Competition dynamics not quantified biochemically
    • In vivo viral challenge with TRIM38 manipulation not performed
  11. 2024 Medium

    Confirmation that TRIM38 K48-ubiquitinates TRAF6 in RANKL-stimulated osteoclasts reinforced TRAF6 as a bona fide TRIM38 substrate and connected TRIM38 to pharmacological modulation of osteoclastogenesis.

    Evidence Co-IP, K48 ubiquitination assays, TRIM38 siRNA knockdown, TRAP staining, bone resorption assay

    PMID:39033726

    Open questions at the time
    • No in vivo bone loss model
    • Precise ubiquitination sites on TRAF6 not mapped
  12. 2025 Medium

    A burst of substrate discoveries (CCT6A, p53, HSPA5, SQSTM1/p62, Zika NS3, TRAF6 crotonylation-enhanced degradation) and in vivo cardiac hypertrophy phenotyping dramatically expanded TRIM38's known target repertoire and functional contexts, including autophagy regulation, cancer suppression, antiviral defense, and cardiac remodeling.

    Evidence Site-specific mutagenesis (CCT6A K127/K138, SQSTM1 K420, TRIM38 K142), Trim38 KO mouse TAC model with TAK1 epistasis, TRIM38 KO cells for ZIKV, crotonylation proteomics, autophagy flux assays, in vivo tumor models

    PMID:40006954 PMID:40047371 PMID:40059473 PMID:40300357 PMID:40314083 PMID:40332097 PMID:41347593

    Open questions at the time
    • Most findings from single labs awaiting independent replication
    • Structural basis for TRIM38 substrate selectivity across diverse targets unknown
    • Relative physiological importance of K63 stabilizing vs K48 degradative activities not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRIM38 achieves substrate selectivity across its remarkably diverse target repertoire, and how its ligase-dependent (K48/K63 ubiquitination) and ligase-independent (lysosomal targeting) activities are differentially engaged in specific cellular contexts, remain open mechanistic questions.
  • No structural model of TRIM38–substrate complexes
  • Post-translational regulation of TRIM38 (beyond IFN induction and crotonylation) incompletely mapped
  • Comprehensive in vivo phenotyping across immune, metabolic, and developmental contexts lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0016874 ligase activity 11
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
CCT6AMITARIG-ISQSTM1TAB2TAB3TRAF6TRIF

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 TRIM38 constitutively interacts with TAB2 and TAB3 (TGF-β-activated kinase 1-binding proteins 2 and 3) 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 treatment, TAB2 localization assays 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 adapter protein TRIF at K228, promoting its proteasomal degradation and thereby negatively regulating TLR3/4-mediated innate immune signaling; additionally, TRIM38 is induced by type I IFNs and in IFN-primed immune cells mediates lysosomal degradation of TAB2 to suppress TNF-α/IL-1β signaling. Trim38 knockout mice, ubiquitination assays (K48-linkage), proteasome inhibitor treatment, type I IFN priming experiments, in vivo LPS/poly(I:C)/Salmonella challenge Journal of immunology High 26392463
2012 TRIM38 targets TRIF (TIR domain-containing adaptor inducing IFN-β), a critical adaptor downstream of TLR3, for K48-linked polyubiquitination and proteasomal degradation; the PRYSPRY domain of TRIM38 interacts with the N-terminus of TRIF, and an intact RING/B-box domain is required for this ubiquitination. Co-immunoprecipitation, domain mapping, overexpression/knockdown, MG132 proteasome inhibition, ubiquitination assays PloS one Medium 23056470
2011 TRIM38 has intrinsic E3 ubiquitin ligase activity, promoting both K48- and K63-linked ubiquitination of cellular proteins and self-ubiquitination; an intact RING domain is essential for this activity. Enterovirus 71 infection induces TRIM38 degradation. In vitro/cellular ubiquitination assays, RING domain mutagenesis, virus infection assays Virology journal Medium 21306652
2024 TRIM38 competes with TRIM25 for binding to RIG-I; TRIM25 activates RIG-I via K63-linked ubiquitination (at K45 of the first CARD domain), while TRIM38 promotes K48-linked ubiquitination and degradation of RIG-I, thereby downregulating IFN-I production in a negative feedback loop. TRIM38's binding region on RIG-I overlaps with and is broader than TRIM25's binding site (aa 25–43 of RIG-I N-terminus). Co-immunoprecipitation, domain mapping, ubiquitination assays (K48/K63 linkage), overexpression/knockdown, reporter assays for IFN-β Inflammation Medium 38630167
2018 TRIM38 mediates lysosome-dependent degradation of TAB2 to inhibit NF-κB activation in osteoclast precursor cells, attenuating RANKL-induced osteoclast formation and NFATc1 expression; conversely, TRIM38 promotes osteoblast differentiation by blocking NF-κB activation. Overexpression/knockdown in osteoclast and osteoblast precursor cells, NF-κB reporter assays, lysosomal degradation assays, marker gene expression Bone Medium 29753717
2017 NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, acting as a docking site to promote TRIM38-mediated lysosomal degradation of TAB2/3 and suppress NF-κB activation. Co-immunoprecipitation, overexpression experiments, cytokine production assays in RA-FLS FEBS letters Medium 28295271
2021 TRIM38 interacts with GLUT1 and promotes its ubiquitination and proteasomal degradation, thereby suppressing glycolytic capacity and tumor progression in bladder cancer. TAP/MS substrate identification, Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in cell lines and xenograft models Journal of translational medicine Medium 34906161
2023 TRIM38 mediates K48-linked ubiquitination of MITA (STING) in M2 macrophages, leading to its degradation and inhibition of pyroptosis, thereby maintaining immune tolerance at the maternal-fetal interface; M1 macrophages show lower TRIM38-mediated MITA ubiquitination and higher MITA levels promoting pyroptosis. Co-immunoprecipitation, K48 ubiquitination assays, macrophage polarization experiments, pyroptosis assays Cell death & disease Medium 38012139
2025 TRIM38 binds to CCT6A and promotes its K48-linked polyubiquitination at K127/K138 residues, leading to CCT6A degradation; loss of TRIM38 elevates CCT6A, which in turn stabilizes c-Myc and activates the MYC pathway, promoting colorectal cancer progression. Co-immunoprecipitation, ubiquitination assays with mutagenesis at K127/K138, overexpression/knockdown, in vivo tumorigenesis model Advanced science Medium 40047371
2025 TRIM38 interacts with HSPA5 (GRP78) and stabilizes it via K63-linked ubiquitination, promoting M2 macrophage polarization (arginase 1 and RORα expression) and suppressing liver inflammation. Co-immunoprecipitation, K63 ubiquitination assay, overexpression in macrophages, single-cell RNA sequencing, functional polarization assays International immunopharmacology Medium 40300357
2025 TRIM38 interacts with Zika virus NS3 protein via its RING domain and promotes lysosome-dependent degradation of NS3, restricting ZIKV replication; deletion of the RING domain abolishes both NS3 interaction and antiviral activity. TRIM38 also upregulates the RIG-I/MDA5 pathway and IFN-β production early in infection. Co-immunoprecipitation, RING domain deletion mutagenesis, lysosome inhibitor assays, TRIM38 KO cells, viral replication assays Viruses Medium 40006954
2025 Trim38 binds to p53 and promotes its ubiquitination-proteasomal degradation; DEHP metabolite MEHP inhibits this Trim38-mediated ubiquitination of p53, resulting in p53 accumulation, cell cycle arrest, and impaired mouse placental trophoblast growth. Co-immunoprecipitation, ubiquitination assay, protein-binding assay (MEHP-Trim38 target identification), transcriptomic and proteomic analysis FASEB journal Medium 40059473
2025 Trim38 negatively regulates the TAK1/JNK/P38 MAPK signaling pathway in cardiomyocytes; Trim38 KO activates TAK1 phosphorylation and downstream JNK/P38 signaling, promoting pathological cardiac hypertrophy, while overexpression suppresses this pathway. Dominant-negative TAK1 rescued Trim38 knockdown-induced hypertrophy, establishing TAK1 as the key downstream target. Trim38 KO mouse model (TAC), cardiomyocyte KD/OE, ubiquitinomics analysis, dominant-negative TAK1 epistasis, western blotting International journal of molecular medicine Medium 40314083
2025 TRIM38 promotes K63-linked ubiquitination of SQSTM1/p62 at K420, which disrupts the interaction between SQSTM1 and LC3, thereby impeding autophagic flux and suppressing breast cancer progression. Co-immunoprecipitation, K63 ubiquitination assays with site-specific mutagenesis (K420), autophagy flux assays, in vitro/in vivo cancer models Advanced science Medium 41347593
2025 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 pathways to facilitate Brucella intracellular survival. Crotonylation proteomics, co-immunoprecipitation, ubiquitination assays, site-specific mutagenesis (K142), signaling pathway analysis International journal of molecular sciences Medium 40332097
2024 TRIM38 mediates K48-linked polyubiquitination of TRAF6 in response to RANKL stimulation, promoting proteasomal degradation of TRAF6 and thereby inhibiting NFATc1 activity and osteoclastogenesis. Co-immunoprecipitation, K48 ubiquitination assays, siRNA knockdown of TRIM38, TRAP staining, bone resorption assay Phytomedicine Medium 39033726
2022 TRIM38 promotes degradation of TRAF6, leading to inactivation of the TAK1/NF-κB signaling pathway, thereby protecting cardiomyocytes from hypoxia/reoxygenation injury; TAK1 inhibitor (5Z-7-oxozeaenol) rescued the aggravated injury seen with TRIM38 deficiency. Adenoviral overexpression/silencing, western blotting for TRAF6 and TAK1/NF-κB pathway, TAK1 inhibitor epistasis, H/R model in H9c2 cells PeerJ Medium 36061751

Source papers

Stage 0 corpus · 27 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 1256 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 85 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) 78 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
2017 NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes. FEBS letters 33 28295271
2021 TRIM38 triggers the uniquitination and degradation of glucose transporter type 1 (GLUT1) to restrict tumor progression in bladder cancer. Journal of translational medicine 30 34906161
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 11 37566200
2022 TRIM38 protects H9c2 cells from hypoxia/reoxygenation injury via the TRAF6/TAK1/NF-κB signalling pathway. PeerJ 9 36061751
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
2025 TRIM38 Suppresses the Progression of Colorectal Cancer via Enhancing CCT6A Ubiquitination to Inhibit the MYC Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40047371
2000 BSPRY, a novel protein of the Ro-Ret family. Biochimica et biophysica acta 6 10978534
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 TRIM38 Inhibits Zika Virus by Upregulating RIG-I/MDA5 Pathway and Promoting Ubiquitin-Mediated Degradation of Viral NS3 Protein. Viruses 4 40006954
2025 E3 ubiquitin ligase TRIM38 regulates macrophage polarization to reduce hepatic inflammation by interacting with HSPA5. International immunopharmacology 4 40300357
2025 The Brucella Effector Protein BspF Crotonylates TRIM38 to Inhibit NF-κB and MAPK Signaling Pathway. International journal of molecular sciences 4 40332097
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 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 2 40059473
2025 Trim38 attenuates pressure overload‑induced cardiac hypertrophy by suppressing the TAK1/JNK/P38 signaling pathway. International journal of molecular medicine 2 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 2 40362389
2025 Tetrahydromagnolol targets TRIM38 to mediate PANoptosis in cancer cells and has the potential for synergistic cancer therapy. Experimental hematology & oncology 1 41476316
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
2025 TRIM38 Suppresses Breast Cancer Progression via Modulating SQSTM1 Ubiquitination and Autophagic Flux. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41347593