Affinage

TRIM35

E3 ubiquitin-protein ligase TRIM35 · UniProt Q9UPQ4

Length
493 aa
Mass
56.5 kDa
Annotated
2026-06-10
38 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM35 (HLS5) is a RING-domain TRIM-family E3 ubiquitin ligase that functions as a tumor suppressor and a substrate-specific regulator of cellular metabolism, innate immune signaling, and cardiovascular homeostasis, originally identified as a chromosome 8p21 candidate tumor suppressor whose enforced expression inhibits growth, clonogenicity, and tumorigenicity (PMID:14662771). A core oncometabolic activity is its control of pyruvate kinase M2: TRIM35 binds PKM2 through its coiled-coil domain, suppresses PKM2 Y105 phosphorylation, and shifts PKM2 toward its tetrameric state, thereby blunting the Warburg effect and tumorigenicity (PMID:25263439, PMID:36196894). Through substrate ubiquitination TRIM35 restrains multiple pro-tumor and pro-glycolytic factors, including K48-linked degradation of PDK1 to inactivate AKT signaling (PMID:35081724), degradation of EIF3E to modulate CDK4/Cyclin D1 (PMID:41429342), and K63-linked ubiquitination of LSD1 at K422 that represses its demethylase activity to enhance IFN-γ signaling and MHC class I expression and tumor immunogenicity (PMID:37979167). TRIM35 also acts directly on chromatin: it binds promoters, monoubiquitinates histone H2B at K120 and histone H3, and recruits p300, thereby remodeling chromatin to control P53 and HSPA6 transcriptional programs (PMID:38860363, PMID:41136372). In innate immunity TRIM35 is a bidirectional regulator, promoting K48-linked degradation of IRF7 to dampen TLR7/9-driven type I interferon as a negative feedback loop (PMID:25907537) and removing K63-linked ubiquitin from STING to attenuate cGAS-STING signaling (PMID:39088122). In the cardiovascular system, cardiomyocyte TRIM35 drives dilated cardiomyopathy by degrading nuclear PKM2 and enhancing P53 output (PMID:36322626, PMID:38860363), while it stabilizes SLC7A5 to activate mTORC1 in cardiac fibroblasts (PMID:39304904) and ubiquitinates RelB in endothelium to restrain MMP10-driven vascular calcification (PMID:39865905).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 Medium

    Established TRIM35/HLS5 as a candidate tumor suppressor, answering whether this 8p21 RBCC protein has growth-regulatory function before any catalytic mechanism was known.

    Evidence cDNA cloning, immunofluorescence localization, and growth/clonogenicity/xenograft assays in HeLa cells

    PMID:14662771

    Open questions at the time
    • No molecular substrate or enzymatic activity defined
    • Mechanism of growth suppression unknown
  2. 2007 Medium

    Linked TRIM35 to transcriptional control by showing its ortholog co-represses GATA-1, addressing how it might influence differentiation programs.

    Evidence Co-IP, subcellular localization, GATA-1 reporter and DNA-binding assays in erythroid differentiation models (mouse ortholog Hls5)

    PMID:18063753

    Open questions at the time
    • Repression mechanism not tied to ubiquitin ligase activity
    • Mouse ortholog data only
  3. 2014 High

    Identified PKM2 as a TRIM35 partner and defined its anti-Warburg activity, revealing how the tumor suppressor reprograms cancer metabolism.

    Evidence Mass spectrometry, reciprocal Co-IP with domain mapping, PKM2 Y105 phosphorylation assay, HCC proliferation and xenograft assays

    PMID:25263439

    Open questions at the time
    • Whether PKM2 regulation requires ubiquitination not resolved here
    • Coiled-coil binding mapped but ligase mechanism on PKM2 unclear
  4. 2015 High

    Defined TRIM35 as a negative feedback regulator of innate immunity by targeting IRF7 for degradation, establishing its E3 ligase role in interferon control.

    Evidence Co-IP, K48-linkage ubiquitination assay, proteasome inhibitor rescue, TLR7/9 stimulation with overexpression/knockdown

    PMID:25907537

    Open questions at the time
    • Ubiquitination site on IRF7 not mapped
    • Single lab
  5. 2021 Medium

    Extended TRIM35 substrate scope to CLOCK and TRAF3, showing context-dependent degradative versus activating ubiquitination in lymphoma and antiviral immunity.

    Evidence Co-IP, ubiquitination assays, IFN-β reporter, NK co-culture, JEV infection model (porcine TRIM35 for TRAF3)

    PMID:34124276 PMID:34626690

    Open questions at the time
    • TRAF3 data is from porcine ortholog
    • Mechanistic depth on NK link and ubiquitin linkage outcomes limited
  6. 2022 High

    Demonstrated TRIM35's role in cardiac and renal pathophysiology and broadened its oncometabolic substrate set, showing the same ligase activity drives disparate disease phenotypes.

    Evidence Cardiomyocyte-specific transgenic and PKM2-KO mice, renal IRI model, Co-IP and ubiquitination assays for PKM2, TIGAR, PDK1; breast cancer PKM2 tetramer assays

    PMID:35081724 PMID:35421414 PMID:36196894 PMID:36322626

    Open questions at the time
    • TIGAR, PDK1 findings are single-lab Medium evidence
    • Tissue-specific determinants of substrate selection unclear
  7. 2023 High

    Revealed non-degradative K63 ubiquitination as a TRIM35 mechanism via LSD1, linking the ligase to chromatin/immunogenicity, and expanded substrates to E1A and IRF5.

    Evidence Co-IP, K63-specific and site-directed ubiquitination assays (LSD1 K422; E1A K253/K285), demethylase activity assay, viral replication and HCC metabolite assays

    PMID:37578239 PMID:37594849 PMID:37979167

    Open questions at the time
    • IRF5 link is single-lab Weak evidence
    • How TRIM35 selects K48 versus K63 linkages not established
  8. 2024 High

    Defined direct histone modification and transporter stabilization activities, showing TRIM35 acts on chromatin (H2B K120 monoubiquitination) and on SLC7A5 to drive cardiac remodeling, and removes K63-Ub from STING.

    Evidence ChIP-seq, cardiomyocyte- and fibroblast-specific transgenic/cKO mice, LC-MS/MS substrate ID, Co-IP, ubiquitination assays, STING RING-domain mutagenesis (C36/C44)

    PMID:38860363 PMID:39088122 PMID:39304904

    Open questions at the time
    • STING deubiquitinase-like activity is Medium single-lab evidence
    • How a RING ligase performs ubiquitin removal mechanistically unresolved
  9. 2025 Medium

    Established TRIM35 as a chromatin-binding transcriptional activator (H3 monoubiquitination, p300 recruitment) and a vascular regulator via RelB, broadening its mechanistic repertoire beyond degradative ubiquitination.

    Evidence ChIP-PCR, endothelial-specific cKO mice, scRNA-seq, Co-IP, K63-ubiquitination of RelB, H3K27ac and MMP10 functional assays

    PMID:39865905 PMID:41136372 PMID:41429342

    Open questions at the time
    • Direct DNA-binding mode and sequence specificity uncharacterized
    • EIF3E finding is Low-confidence single lab
    • Non-proteolytic H3 ubiquitination mechanism novel and unreplicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single RING-domain ligase achieves its broad substrate range and switches between K48-degradative, K63-non-degradative, monoubiquitinating, and ubiquitin-editing activities in a tissue- and context-specific manner.
  • No structural model of substrate recognition
  • Determinants of linkage-type and proteolytic versus non-proteolytic outcomes unknown
  • Direct DNA-binding specificity undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 10 GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 5 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9612973 Autophagy 1
Partners
IRF7LSD1PDK1PKM2RELBSLC7A5STING1TIGAR

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 TRIM35 physically interacts with pyruvate kinase isoform M2 (PKM2) via its coiled-coil domain, suppresses PKM2 tyrosine-105 (Y105) phosphorylation, and thereby reduces the Warburg effect and tumorigenicity in hepatocellular carcinoma cells. Mass spectrometry, Co-IP, domain deletion mutants, PKM2 Y105 phosphorylation assay, HCC cell proliferation and xenograft assays Oncogene High 25263439
2015 TRIM35 negatively regulates TLR7/9-mediated type I interferon production by interacting with IRF7, promoting its K48-linked polyubiquitination, and inducing its proteasome-dependent degradation, acting as a negative feedback regulator. Co-IP, ubiquitination assay (K48-linkage), proteasome inhibitor rescue, TLR7/9 stimulation assays, overexpression/knockdown FEBS letters High 25907537
2022 TRIM35 ubiquitinates PKM2 and regulates the transition between its tetrameric (active, high-affinity) and dimeric (less active) forms, thereby suppressing the Warburg effect in breast cancer cells. Ubiquitination assays, co-IP, PKM2 tetramer/dimer gel assays, cell proliferation/migration/invasion assays, xenograft International journal of oncology Medium 36196894
2022 TRIM35, acting as an E3 ubiquitin ligase, promotes K48-linked ubiquitination and proteasomal degradation of nuclear PKM2 (S37P-PKM2) in cardiomyocytes; cardiomyocyte-specific TRIM35 overexpression in mice reduces nuclear PKM2 and GATA4/6 levels while increasing P53, producing dilated cardiomyopathy. Cardiomyocyte-specific TRIM35 transgenic mice, PKM2 cardiac-specific knockout mice, ubiquitination assays, Co-IP, cardiac echocardiography, IHC, patient LV samples Science translational medicine High 36322626
2021 TRIM35 functions as an E3 ubiquitin ligase to mediate the ubiquitination and degradation of CLOCK, a key regulator of circadian rhythmicity, in diffuse large B-cell lymphoma (DLBCL) cells, suppressing DLBCL proliferation and modulating NK cell infiltration. Overexpression in DLBCL cell lines, ubiquitination assay, co-IP, NK cell co-culture/infiltration assays, tumor xenograft Journal of immunology research Medium 34124276
2022 TRIM35 interacts with TIGAR and promotes its polyubiquitination and proteasomal degradation; TRIM35 knockdown alleviates renal ischemia-reperfusion injury by reducing oxidative stress and enhancing mitochondrial fusion via stabilization of TIGAR. Co-IP, ubiquitination assay, TRIM35 knockdown (siRNA), mitochondrial morphology analysis, oxidative stress assays, renal IRI mouse model International journal of biological macromolecules Medium 35421414
2022 TRIM35 promotes breast cancer cell apoptosis by ubiquitinating and degrading PDK1, leading to inactivation of AKT signaling. Ubiquitination assay, co-IP, overexpression/knockdown, AKT pathway western blot, xenograft mouse model Neoplasma Medium 35081724
2023 TRIM35 (E3 ligase) mediates K63-linked ubiquitination of LSD1 at lysine-422, repressing LSD1 demethylase activity; suppressed LSD1 activity facilitates ERGIC1 transcription, autophagy inhibition, and IFNGR1 stabilization, activating IFN-γ signaling and increasing MHC class I expression in NSCLC cells. Co-IP, K63-specific ubiquitination assay, LSD1 demethylase activity assay, site-directed mutagenesis (K422), gene expression analysis, NSCLC cell and mouse models Cell reports High 37979167
2024 TRIM35 directly monoubiquitinates lysine-120 (K120) on histone H2B in postnatal cardiomyocytes, promoting chromatin remodeling and accessibility of P53 to its transcriptional promoter targets, thereby increasing P53 transcriptional output and contributing to dilated cardiomyopathy. ChIP-seq, RNA-seq, overexpression transgenic mice (cardiomyocyte-specific), siRNA knockdown in primary cardiomyocytes, adenovirus-mediated gene delivery, patient DCM LV samples Circulation research High 38860363
2024 TRIM35 interacts with and ubiquitinates SLC7A5 (an amino acid transporter), increasing its stability and enhancing amino acid transport, which activates mTORC1 signaling in cardiac fibroblasts to promote fibroblast proliferation, migration, and differentiation, driving cardiac remodeling. LC-MS/MS substrate identification, Co-IP, ubiquitination assay, fibroblast-specific Trim35 conditional knockout mice (TAC surgery), adenoviral/AAV overexpression, mTORC1 pathway assays, RNA-seq Cell communication and signaling High 39304904
2023 TRIM35 interacts with adenovirus E1A protein and promotes its K48-linked ubiquitination at lysine residues K253 and K285, leading to E1A degradation and inhibition of HAdV replication. Co-IP, K48-linked ubiquitination assay, site-directed mutagenesis of E1A (K253A, K285A), viral replication assays, shTRIM35 oncolytic adenovirus construct Journal of virology Medium 37578239
2024 TRIM35 negatively regulates the cGAS-STING antiviral signaling pathway by directly interacting with STING and removing K63-linked ubiquitin from STING via its RING domain (C36 and C44 sites acting as deubiquitinase-like activity), impairing STING interaction with TBK1/IKKε and attenuating IFN-β production. Co-IP, co-localization (cytoplasm), K63-ubiquitin assay, RING domain mutagenesis (C36A, C44A), TBK1/IKKε interaction assays, IFN-β reporter assay Inflammation Medium 39088122
2021 Porcine TRIM35 directly interacts with TRAF3 and catalyzes K63-linked polyubiquitination of TRAF3, leading to upregulation of IFN-β production; RING and PRY/SPRY domains are essential for E3 ligase activity. Co-IP, K63-linked ubiquitination assay, domain deletion mutants (RING, PRY/SPRY), IFN-β luciferase reporter, overexpression/knockdown in ST cells, JEV infection model Developmental and comparative immunology Medium 34626690
2023 TRIM35 interacts with IRF5 and promotes its ubiquitination and degradation; loss of TRIM35 leads to increased IRF5 levels and enhanced LDHA expression and glycolysis in hepatocellular carcinoma cells. Co-immunoprecipitation, ubiquitination assay, mass spectrometry metabolite analysis, western blot, qPCR, HCC cell functional assays Journal of digestive diseases Medium 37594849
2007 Hls5 (mouse ortholog of TRIM35/HLS5) relocalizes from cytoplasmic granules to the nucleus under GATA-1 influence, associates with both FOG-1 and GATA-1, and suppresses GATA-1-mediated transactivation and GATA-1 DNA binding, thereby impeding erythroid maturation. Co-IP (Hls5/FOG-1/GATA-1), subcellular localization (fluorescence microscopy), GATA-1 transactivation reporter assay, GATA-1 DNA binding assay (ChIP/EMSA), erythroid differentiation assays Blood Medium 18063753
2003 HLS5 (human TRIM35), an RBCC family protein, localizes to cytoplasmic granules and punctate nuclear bodies; enforced expression in HeLa cells inhibits cell growth, clonogenicity, and tumorigenicity, establishing it as a candidate tumor suppressor at chromosome 8p21. cDNA cloning, subcellular localization (immunofluorescence), HeLa cell overexpression, growth inhibition and colony-formation assays, xenograft tumorigenicity assays The Journal of biological chemistry Medium 14662771
2025 TRIM35 directly binds genomic promoters (DNA-binding activity), interacts with histone H3, and catalyzes non-proteolytic (monoubiquitination) ubiquitination of H3, serving as a recruitment signal for p300 acetyltransferase, leading to H3K27 acetylation and transcriptional activation of HSPA6, which suppresses breast cancer progression. ChIP-PCR, Co-IP, ubiquitination assay (non-proteolytic), p300 recruitment assay, H3K27ac western blot, HSPA6 expression analysis, breast cancer cell functional assays Cell death discovery Medium 41136372
2025 Endothelial TRIM35 inhibits MMP10 expression and secretion by promoting K63-linked ubiquitination of RelB and maintaining its nuclear localization, thereby suppressing noncanonical NF-κB-driven MMP10 transcription; TRIM35 endothelial-specific conditional knockout leads to increased MMP10 release and promotes vascular graft calcification via SMC paracrine signaling. Endothelial-specific TRIM35 cKO mice (arterial isograft model), single-cell RNA-seq, Co-IP, K63-ubiquitination assay of RelB, RelB nuclear localization assay, MMP10 ELISA, in vitro SMC calcification co-culture Advanced science Medium 39865905
2025 TRIM35 ubiquitinates EIF3E and promotes its degradation, modulating the CDK4/Cyclin D1 signaling pathway to suppress endometrial cancer cell proliferation. Co-IP, ubiquitination assay, EIF3E overexpression rescue, CDK4/Cyclin D1 western blot, cell proliferation and invasion assays Cellular signalling Low 41429342

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and MAIR-II, regulate mast cell and macrophage activation. The Journal of experimental medicine 85 12874256
2014 TRIM35 Interacts with pyruvate kinase isoform M2 to suppress the Warburg effect and tumorigenicity in hepatocellular carcinoma. Oncogene 78 25263439
2015 Co-expression of PKM2 and TRIM35 predicts survival and recurrence in hepatocellular carcinoma. Oncotarget 66 25576919
2017 miR-4417 Targets Tripartite Motif-Containing 35 (TRIM35) and Regulates Pyruvate Kinase Muscle 2 (PKM2) Phosphorylation to Promote Proliferation and Suppress Apoptosis in Hepatocellular Carcinoma Cells. Medical science monitor : international medical journal of experimental and clinical research 35 28394882
2015 TRIM35 negatively regulates TLR7- and TLR9-mediated type I interferon production by targeting IRF7. FEBS letters 32 25907537
2022 TRIM35 ubiquitination regulates the expression of PKM2 tetramer and dimer and affects the malignant behaviour of breast cancer by regulating the Warburg effect. International journal of oncology 28 36196894
2008 Caspase-independent cell death by CD300LF (MAIR-V), an inhibitory immunoglobulin-like receptor on myeloid cells. Journal of immunology (Baltimore, Md. : 1950) 28 18097021
2003 HLS5, a novel RBCC (ring finger, B box, coiled-coil) family member isolated from a hemopoietic lineage switch, is a candidate tumor suppressor. The Journal of biological chemistry 28 14662771
2022 TRIM35-mediated degradation of nuclear PKM2 destabilizes GATA4/6 and induces P53 in cardiomyocytes to promote heart failure. Science translational medicine 26 36322626
2007 Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP12 and FcRgamma chain on peritoneal macrophages. Journal of immunology (Baltimore, Md. : 1950) 25 17202337
2023 E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC. Cell reports 23 37979167
2017 Fish TRIM35 negatively regulates the interferon signaling pathway in response to grouper nodavirus infection. Fish & shellfish immunology 20 28823982
2014 Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated inflammatory monocyte migration. Nature communications 20 25134989
2009 Regulation of Immune Responses by the Activating and Inhibitory Myeloid-Associate Immunoglobuline-Like Receptors (MAIR) (CD300). Immune network 19 20107542
2007 Activation of neutrophils by a novel triggering immunoglobulin-like receptor MAIR-IV. Molecular immunology 19 17543387
2022 TRIM35 functions as a novel tumor suppressor in breast cancer by inducing cell apoptosis through ubiquitination of PDK1. Neoplasma 18 35081724
2004 Requirement of the tyrosines at residues 258 and 270 of MAIR-I in inhibitory effect on degranulation from basophilic leukemia RBL-2H3. International immunology 17 15569773
2021 Suppression of DLBCL Progression by the E3 Ligase Trim35 Is Mediated by CLOCK Degradation and NK Cell Infiltration. Journal of immunology research 14 34124276
2022 The inhibition of TRIM35-mediated TIGAR ubiquitination enhances mitochondrial fusion and alleviates renal ischemia-reperfusion injury. International journal of biological macromolecules 13 35421414
2024 TRIM35 Monoubiquitinates H2B in Cardiac Cells, Implications for Heart Failure. Circulation research 12 38860363
2024 TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts. Cell communication and signaling : CCS 12 39304904
2023 IRF5 promotes glycolysis in the progression of hepatocellular carcinoma and is regulated by TRIM35. Journal of digestive diseases 12 37594849
2021 Porcine TRIM35 positively regulate TRAF3-mediated IFN-β production and inhibit Japanese encephalitis virus replication. Developmental and comparative immunology 9 34626690
2020 MAIR-II deficiency ameliorates cardiac remodelling post-myocardial infarction by suppressing TLR9-mediated macrophage activation. Journal of cellular and molecular medicine 8 33140535
2023 Inhibition of human adenovirus replication by TRIM35-mediated degradation of E1A. Journal of virology 6 37578239
2008 Expression of a splicing isoform of MAIR-V (CD300LF), an inhibitory immunoglobulin-like receptor on myeloid cells. Hybridoma (2005) 6 18294079
2025 Downregulated TRIM35 Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress and Inflammation via Inhibiting TLR4/NF-κB Pathway. Cardiovascular drugs and therapy 4 39954170
2007 Hls5 regulated erythroid differentiation by modulating GATA-1 activity. Blood 4 18063753
2020 Tripartite motif-containing 35 (TRIM35) is up-regulated in UUO-induced renal fibrosis animal model. Histology and histopathology 3 32955098
2022 Duck TRIM35 Promotes Tembusu Virus Replication by Interfering with RIG-I-Mediated Antiviral Signaling in Duck Embryo Fibroblasts. Microbiology spectrum 2 36445078
2025 Endothelial TRIM35-Regulated MMP10 Release Exacerbates Calcification of Vascular Grafts. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 39865905
2025 TRIM35, a novel DNA-binding protein, epigenetically modifies H3 to promote HSPA6 transcription and suppress breast cancer progression. Cell death discovery 1 41136372
2024 HBO regulates the Warburg effect of hypoxic HCC cells through miR-103a-3p/TRIM35. Discover oncology 1 38642184
2017 Retracted: Mice lacking the Raf-1 kinase inhibitor protein exhibit exaggerated hypoxia-induced pulmonary hypertension, by I Morecroft, B Doyle, M Nilsen, W Kolch, K Mair and MR MacLean. British Journal of Pharmacology, volume 163(5): 948-963, published in June 2011; DOI 10.1111/j.1476-5381.2011.01305.x. British journal of pharmacology 1 28397257
2026 Knockdown of TRIM35 suppresses cell proliferation and metastasis by modulating the PPAR signalling pathway in papillary thyroid cancer cells. Translational cancer research 0 42180910
2025 tsRNA-3040b accumulates R-loop to regulate Trim35 transcription, which leads to disordered glycolysis and promotes PAECs proliferation. Cellular & molecular biology letters 0 41351040
2025 TRIM35 inhibits endometrial cancer progression via ubiquitination and degradation of EIF3E. Cellular signalling 0 41429342
2024 TRIM35 Negatively Regulates the cGAS-STING-Mediated Signaling Pathway by Attenuating K63-Linked Ubiquitination of STING. Inflammation 0 39088122

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