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TRIM41

E3 ubiquitin-protein ligase TRIM41 · UniProt Q8WV44

Length
630 aa
Mass
71.7 kDa
Annotated
2026-04-28
13 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM41 (also known as RINCK) is a RING-finger E3 ubiquitin ligase that targets a broad array of substrates for proteasomal degradation, functioning in innate antiviral defense, transcriptional regulation, genome stability, and meiotic chromosome dynamics. It ubiquitinates viral nucleoproteins (influenza A NP via its SPRY domain, VSV N protein) to restrict infection, catalyzes K63-linked polyubiquitination of BCL10 to activate NF-κB/TBK1-IRF3 signaling, and monoubiquitinates cGAS to enhance cGAMP synthesis and type I interferon production (PMID:29899090, PMID:33640899, PMID:29760876). Beyond immunity, TRIM41 degrades the transcription factor ZSCAN21 to regulate α-synuclein transcription, ubiquitinates LINE-1 ORF2p in a cGAS/CHK2-dependent manner to suppress retrotransposition, promotes K48-linked ubiquitination of NRF2 to suppress antioxidant responses, and is scaffolded by circRNA_0067717 to ubiquitinate p53 (PMID:30485814, PMID:38086852, PMID:37844381, PMID:36705889). Its E3 ligase activity is also required during male meiosis, where TRIM41 localizes to chromosome axes and regulates SYCP3 loading; loss of RING domain function causes SYCP3 overaccumulation on meiotic chromosomes (PMID:35648791).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2005 Medium

    Determining where TRIM41 acts in the cell established that it forms nuclear and cytoplasmic speckles, with nuclear entry mediated by an N-terminal segment independent of a classical NLS.

    Evidence GFP-fusion imaging and deletion mapping in cultured cells

    PMID:16022281

    Open questions at the time
    • Single study without independent replication
    • Identity of nuclear speckle compartment undefined
    • Mechanism of NLS-independent nuclear import not determined
  2. 2007 High

    Identification of TRIM41 as an E3 ubiquitin ligase that targets PKC isoforms via their C1A domain for proteasomal degradation established TRIM41's fundamental enzymatic activity and first substrate class.

    Evidence Yeast two-hybrid, reciprocal co-IP, in vitro ubiquitination, and genetic knockdown in cells

    PMID:17893151

    Open questions at the time
    • Physiological context for PKC regulation by TRIM41 not defined
    • Ubiquitin chain type on PKC not specified
  3. 2018 High

    Demonstrating that TRIM41 ubiquitinates influenza A NP via its SPRY domain and restricts viral replication revealed TRIM41 as a direct antiviral effector, with concurrent work showing it monoubiquitinates cGAS to amplify innate immune signaling.

    Evidence In vitro ubiquitination, SPRY domain mapping, CRISPR KO, E3-dead mutant for IAV NP; CRISPR deletion and cGAMP synthesis assay for cGAS

    PMID:29760876 PMID:29899090

    Open questions at the time
    • Relative contribution of direct NP degradation versus cGAS-mediated signaling to antiviral defense unclear
    • Monoubiquitination site on cGAS not mapped
  4. 2018 High

    Showing that TRIM41 degrades the transcription factor ZSCAN21 to regulate SNCA expression expanded its substrate repertoire to transcriptional regulation and implicated it in α-synuclein biology.

    Evidence Ubiquitination assays, knockdown/overexpression, SNCA reporter, TRIM17 epistasis

    PMID:30485814

    Open questions at the time
    • Whether TRIM41-ZSCAN21 axis is relevant in dopaminergic neurons in vivo not tested
    • Ubiquitin linkage type on ZSCAN21 not specified
  5. 2020 High

    Extension of the antiviral ubiquitination mechanism to VSV N protein confirmed TRIM41 as a broad-spectrum antiviral E3 ligase acting on viral nucleoproteins.

    Evidence In vitro/cellular ubiquitination, RNAi, E3-dead mutant complementation for VSV

    PMID:31979016

    Open questions at the time
    • Range of viral nucleoproteins targeted by TRIM41 not systematically tested
    • Whether SPRY domain mediates VSV N recognition (as for IAV NP) not confirmed
  6. 2021 High

    Identification of K63-linked polyubiquitination of BCL10 by TRIM41, enabling NEMO recruitment and NF-κB/TBK1 activation, established a non-degradative ubiquitin signaling role in innate immunity distinct from its degradative functions.

    Evidence K63-specific ubiquitination assay, TRIM41-KO macrophages, in vivo KO, viral infection assays

    PMID:33640899

    Open questions at the time
    • How TRIM41 distinguishes between K48 and K63 chain assembly on different substrates is unknown
    • Redundancy with other BCL10 E3 ligases not assessed
  7. 2022 High

    Genetic analysis in mice revealed that TRIM41 RING-domain E3 activity is required during meiosis to prevent SYCP3 overloading on chromosome axes, establishing a germ-cell-specific developmental function.

    Evidence Trim41 KO and ΔRING knock-in mouse models with meiotic spread immunostaining

    PMID:35648791

    Open questions at the time
    • Whether SYCP3 is a direct ubiquitination substrate of TRIM41 not demonstrated
    • Impact on male fertility not fully characterized
    • Mechanism linking TRIM41 to SYCP3 dynamics (direct vs. indirect) unresolved
  8. 2023 High

    Discovery that TRIM41 ubiquitinates LINE-1 ORF2p in a CHK2/cGAS-dependent manner revealed a DNA-damage-responsive genome defense axis, linking TRIM41 to retrotransposon suppression.

    Evidence Co-IP, ubiquitination assay, phospho-site mapping on cGAS, CRISPR KO, retrotransposition reporter

    PMID:38086852

    Open questions at the time
    • Whether this axis operates in germ cells or early embryos not tested
    • Structural basis for cGAS-enhanced TRIM41–ORF2p interaction unknown
  9. 2023 Medium

    Parallel studies identified NRF2 (K48-linked ubiquitination) and p53 (scaffolded by circRNA_0067717) as additional degradative substrates, broadening TRIM41's role to oxidative stress responses and tumor suppressor regulation.

    Evidence K48-linkage ubiquitination and IEC-specific KO/OE mice for NRF2; RNA pull-down, RIP, and deletion mapping for circRNA-p53 axis

    PMID:36705889 PMID:37844381

    Open questions at the time
    • NRF2 finding from single lab; independent replication needed
    • circRNA_0067717 scaffolding model awaits reconstitution with purified components
    • Whether TRIM41 ubiquitinates p53 independently of circRNA scaffold not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying structural and regulatory framework explaining how TRIM41 selects among its many substrates and switches between K48 and K63 ubiquitin linkage types remains unknown.
  • No crystal or cryo-EM structure of TRIM41 or any TRIM41–substrate complex
  • Substrate selection logic (SPRY vs. other domains) not comprehensively mapped
  • Upstream signals controlling TRIM41 expression, stability, or activity are poorly defined
  • Physiological relevance of many substrates (PKC, PKD1, c-Maf) lacks in vivo genetic validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016874 ligase activity 5
Localization
GO:0005634 nucleus 1 GO:0005694 chromosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 2 R-HSA-1474165 Reproduction 1
Partners
BCL10CGASL1RE1NRF2PRKCATP53TRIM17ZSCAN21

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 TRIM41 (RINCK) was identified as an E3 ubiquitin ligase that interacts with the C1A domain of PKC isoforms (conventional, novel, and atypical) and ubiquitinates PKC both in vitro and in cells, leading to proteasomal degradation and reduced PKC levels; genetic knockdown of RINCK increased PKC levels, and this mechanism was independent of classic phorbol ester-mediated PKC down-regulation. Yeast two-hybrid screen, co-immunoprecipitation, in vitro and cellular ubiquitination assays, genetic knockdown The Journal of biological chemistry High 17893151
2005 TRIM41 protein (isoforms alpha and beta) localizes as speckles in both the cytoplasm and nucleus; nuclear transport is mediated by an N-terminal segment common to both isoforms, independent of a classical nuclear localization signal. GFP fusion live-cell imaging, Western blot of cellular fractions, deletion construct mapping Molecular biology reports Medium 16022281
2018 TRIM41 interacts with influenza A virus nucleoprotein (NP) through its SPRY domain, ubiquitinates NP in vitro and in cells, leading to proteasomal degradation of NP and restriction of IAV infection; an E3 ligase-dead TRIM41 mutant failed to restrict infection. Co-immunoprecipitation, in vitro and cellular ubiquitination assays, RNAi/CRISPR knockout, overexpression, E3-dead mutant complementation Journal of virology High 29899090
2018 TRIM41 (RINCK) binds to cGAS and promotes its monoubiquitination, positively regulating cGAS-mediated cGAMP synthesis and downstream TBK1/IRF3 phosphorylation and type I interferon production in response to cytosolic DNA; CRISPR deletion of RINCK dampened interferon production. CRISPR/Cas9 deletion, co-immunoprecipitation, ubiquitination assay, cGAMP synthesis assay, TBK1/IRF3 phosphorylation readout Cell & bioscience High 29760876
2018 TRIM41 functions as an E3 ubiquitin ligase for the transcription factor ZSCAN21, targeting it for ubiquitin-mediated degradation, thereby regulating SNCA (α-synuclein) transcription; TRIM17 counteracts this by decreasing TRIM41-mediated ZSCAN21 degradation. Ubiquitination assays, knockdown/overexpression with protein stability readout, reporter assays for SNCA transcription, genetic variant expression Cell reports High 30485814
2020 TRIM41 interacts with VSV nucleoprotein (N protein), ubiquitinates it both in vitro and in cells, and promotes its proteasomal degradation, thereby restricting VSV infection; E3 ligase-dead TRIM41 mutant failed to restrict VSV. Co-immunoprecipitation, in vitro and cellular ubiquitination assays, overexpression, RNAi knockdown, E3-dead mutant complementation Viruses High 31979016
2021 TRIM41 directly interacts with BCL10 and catalyzes K63-linked polyubiquitination of BCL10, enabling NEMO recruitment and activation of NF-κB and TBK1-IRF3 pathways during innate antiviral responses; TRIM41 deficiency impaired cytokine and type I interferon production in macrophages. Co-immunoprecipitation, ubiquitination linkage assays, TRIM41-KO macrophages, viral infection assays, in vivo knockout Signal transduction and targeted therapy High 33640899
2021 TRIM41 targets PKD1 for ubiquitin-mediated proteasomal degradation; ANXA10 interacts with PKD1 and inhibits TRIM41-mediated PKD1 degradation, with consequences for SMAD6 levels and melanoma cell migration. Co-immunoprecipitation, protein stability assay, ANXA10 knockout, Western blot Cancer letters Medium 34324862
2022 TRIM41 E3 ubiquitin ligase activity (via its RING domain) is required for proper chromosome axis protein dynamics during male meiosis; Trim41 KO and RING-domain deletion mice both exhibited SYCP3 overloading on chromosome axes (especially X chromosome), and ΔRING-TRIM41 accumulated on chromosome axes, indicating TRIM41 acts on the chromosome axis to regulate SYCP3 levels. Trim41 knockout, RING-domain deletion knock-in mouse, immunostaining of meiotic spreads, co-localization of mutant TRIM41 on axes PLoS genetics High 35648791
2023 TRIM41 interacts with LINE-1 ORF2p and ubiquitinates it to promote its degradation; nuclear cGAS enhances the association between ORF2p and TRIM41, and this is potentiated by CHK2-mediated phosphorylation of cGAS at S120 and S305 following DNA damage, forming a CHK2-cGAS-TRIM41-ORF2p regulatory axis that suppresses L1 retrotransposition. Co-immunoprecipitation, ubiquitination assay, phosphorylation mapping, CRISPR/KO, retrotransposition reporter assay, cancer mutant analysis Nature communications High 38086852
2023 circRNA_0067717 acts as a molecular scaffold that simultaneously binds TRIM41 (at the 301-425 nt region) and p53 (at the 1-176 nt region), facilitating TRIM41-mediated ubiquitination and degradation of p53. RNA pull-down, RNA immunoprecipitation, RNA FISH, deletion mapping of binding regions, ubiquitination and protein stability assays Cellular oncology Medium 36705889
2023 TRIM41 (RINCK) directly interacts with NRF2 and promotes its K48-linked ubiquitination and proteasomal degradation, suppressing NRF2 nuclear translocation and antioxidant defense in intestinal epithelial cells; IEC-specific Trim41 KO or overexpression modulated colitis severity in mice. Co-immunoprecipitation, K48-linkage ubiquitination assay, IEC-specific KO and OE mouse models, in vivo colitis models Phytomedicine Medium 37844381
2024 TRIM41 promotes ubiquitin-mediated degradation of c-Maf in airway dendritic cells, reducing IL-10 expression and compromising tolerogenic DC function, thereby contributing to airway allergy pathogenesis. TRIM41 expression analysis in airway DCs, functional assays with TRIM41 inhibition, c-Maf and IL-10 readouts iScience Low 38883815

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection. Journal of virology 76 29899090
2018 RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses. Cell & bioscience 55 29760876
2007 Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase. The Journal of biological chemistry 53 17893151
2023 Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation. Nature communications 36 38086852
2018 The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21. Cell reports 34 30485814
2020 TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Vesicular Stomatitis Virus Infection. Viruses 24 31979016
2021 TRIM41 is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO. Signal transduction and targeted therapy 22 33640899
2023 circRNA_0067717 promotes paclitaxel resistance in nasopharyngeal carcinoma by acting as a scaffold for TRIM41 and p53. Cellular oncology (Dordrecht, Netherlands) 20 36705889
2021 ANXA10 promotes melanoma metastasis by suppressing E3 ligase TRIM41-directed PKD1 degradation. Cancer letters 19 34324862
2023 Ochratoxin A promotes chronic enteritis and early colorectal cancer progression by targeting Rinck signaling. Phytomedicine : international journal of phytotherapy and phytopharmacology 10 37844381
2005 Intracellular localization and domain organization of human TRIM41 proteins. Molecular biology reports 7 16022281
2024 TRIM41 contributes to the pathogenesis of airway allergy by compromising dendritic cells' tolerogenic properties. iScience 1 38883815
2022 Trim41 is required to regulate chromosome axis protein dynamics and meiosis in male mice. PLoS genetics 1 35648791