Affinage

TRIM40

E3 ubiquitin ligase TRIM40 · UniProt Q6P9F5

Length
258 aa
Mass
29.3 kDa
Annotated
2026-04-28
16 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM40 is a RING domain-containing E3 ubiquitin ligase that functions as a broad negative regulator of innate immune signaling and inflammatory pathways while also modulating cytoskeletal and hypertrophic responses through substrate-specific ubiquitination. It suppresses NF-κB signaling by promoting neddylation of IKKγ via its RING domain (PMID:21474709), and inhibits RIG-I/MDA5-mediated antiviral interferon responses by catalyzing K27- and K48-linked polyubiquitination that targets these sensors for proteasomal degradation, a process facilitated by the upstream kinase Riok3 (PMID:29117565, PMID:34161773). TRIM40 also ubiquitinates ROCK1 through its RING, B-box, and C-terminal domains, disrupting cortical actin signaling and epithelial barrier integrity, with Trim40-deficient mice showing resistance to experimental colitis (PMID:36755029); additional substrates include NLRP3 (suppressing inflammasome activation) (PMID:34763147), DAB1 (PMID:37146559), and Keap1 (activating Nrf2-dependent antioxidant responses) (PMID:38901248). Beyond degradative K48-linked ubiquitination, TRIM40 catalyzes K63-linked ubiquitination of PKN2 via its B-box domain in a C29-dependent manner, activating PKN2 phosphorylation and driving pathological cardiac hypertrophy (PMID:41572508).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Establishing TRIM40 as a RING-dependent modifier of NF-κB signaling resolved the question of whether this uncharacterized TRIM family member possessed enzymatic activity; it was shown to promote neddylation (not canonical ubiquitination) of IKKγ, inhibiting NF-κB.

    Evidence Co-IP, neddylation assay, ΔRING dominant-negative, and siRNA knockdown with NF-κB reporter in human cells

    PMID:21474709

    Open questions at the time
    • Neddylation linkage site on IKKγ not mapped
    • Whether TRIM40 also ubiquitinates IKKγ was not tested
    • Physiological context (tissue, stimulus) for this regulation was unclear
  2. 2017 High

    Demonstrating that TRIM40 directly ubiquitinates RIG-I and MDA5 with K27/K48 linkages for proteasomal degradation established it as a negative regulator of antiviral innate immunity, with in vivo validation in knockout mice.

    Evidence Reciprocal Co-IP, linkage-specific ubiquitination assay, proteasome inhibitor rescue, TRIM40 KO mice challenged with virus

    PMID:29117565

    Open questions at the time
    • Mechanism of substrate recognition (which domain contacts RIG-I/MDA5) not defined
    • Whether additional upstream signals regulate TRIM40 activity was unknown
  3. 2021 High

    Identifying Riok3 as an upstream recruiter of TRIM40 to RIG-I/MDA5 answered how TRIM40 is directed to its substrates, establishing a Riok3–TRIM40 axis for suppression of type I IFN signaling.

    Evidence Co-IP, ubiquitination assay, myeloid-specific Riok3 KO mice with viral challenge

    PMID:34161773

    Open questions at the time
    • Whether Riok3 phosphorylates TRIM40 or acts purely as a scaffold was not resolved
    • Structural basis for Riok3–TRIM40 interaction unknown
  4. 2021 Medium

    Showing TRIM40 ubiquitinates NLRP3 in a RING-dependent manner to suppress inflammasome activation extended its immunosuppressive function beyond RLR signaling to inflammasome regulation.

    Evidence Co-IP, ubiquitination assay, ΔRING mutant, siRNA in glomerular mesangial cells

    PMID:34763147

    Open questions at the time
    • Ubiquitin linkage type on NLRP3 not specified
    • In vivo validation absent
    • Single lab, not independently replicated
  5. 2023 High

    Identifying ROCK1 as a TRIM40 substrate requiring RING, B-box, and C-terminal domains for ubiquitination and degradation revealed a non-immune function — regulation of cortical actin and epithelial barrier integrity — with Trim40 KO mice protected from colitis.

    Evidence Domain deletion mutants, ubiquitination assay, TRIM40 KO mice in DSS colitis model

    PMID:36755029

    Open questions at the time
    • Ubiquitin linkage type on ROCK1 not specified in this study
    • How TRIM40 expression is regulated in intestinal epithelium unknown
  6. 2023 Medium

    Extending the ROCK1 axis, TRIM40 was found to ubiquitinate DAB1 (K48 linkage) suppressing Reelin/PI3K/AKT signaling in diabetic retinopathy, and independently shown to degrade Keap1, activating Nrf2 antioxidant responses, broadening the substrate repertoire to metabolic and oxidative stress contexts.

    Evidence Co-IP and K48-ubiquitination assay with AAV-mediated TRIM40 in diabetic mice (DAB1); Co-IP, ubiquitination, and xenograft models (Keap1)

    PMID:37146559 PMID:38901248

    Open questions at the time
    • DAB1 and Keap1 studies from single labs, not independently confirmed
    • Domain requirements for DAB1 and Keap1 recognition not mapped
  7. 2024 Medium

    Connecting HCV-induced EGFR core fucosylation to TRIM40-mediated K48 ubiquitination of RIG-I provided a viral immune-evasion mechanism, though TRIM40 itself was not directly mutagenized in this context.

    Evidence K48-linkage-specific ubiquitination assay, EGFR glycosylation mutants, FUT8 inhibitor, viral replication assay

    PMID:38253527

    Open questions at the time
    • TRIM40 role inferred from pathway context without direct TRIM40 mutagenesis in this study
    • Whether fucosylated EGFR directly modulates TRIM40 expression or activity not established
  8. 2025 Medium

    Identification of Rnd3 as a second co-regulator that facilitates TRIM40–ROCK1 interaction in cardiac microvascular endothelial cells revealed that context-specific adaptors control TRIM40 substrate access, paralleling the Riok3 mechanism for RLR targets.

    Evidence Co-IP, ubiquitination assay, Rnd3 overexpression in diabetic mouse model

    PMID:39792251

    Open questions at the time
    • Direct binding interface between Rnd3 and TRIM40 not defined
    • Single lab, single study
  9. 2026 High

    Demonstrating that TRIM40 catalyzes K63-linked (non-degradative) ubiquitination of PKN2 via its B-box domain, activating PKN2 phosphorylation and driving cardiac hypertrophy, established that TRIM40 is not exclusively a degradative E3 ligase and functions in pathological cardiac remodeling.

    Evidence B-box domain mapping, C29 active-site mutant, K63-linkage-specific ubiquitination, TRIM40 KO and overexpression mice with Ang II/TAC hypertrophy, pharmacological PKN2 inhibition

    PMID:41572508

    Open questions at the time
    • Structural basis for K63 vs K48 linkage selectivity by TRIM40 unknown
    • Whether specific E2 conjugating enzymes dictate linkage type not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanistic basis by which TRIM40 selects ubiquitin chain linkage type (K48 degradative vs K63 activating vs neddylation) and how tissue-specific co-regulators (Riok3, Rnd3) dictate substrate selectivity remain unresolved.
  • No structural model of TRIM40 or TRIM40–substrate complexes exists
  • E2 conjugating enzyme partners not identified
  • Transcriptional and post-translational regulation of TRIM40 itself poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 4
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 3
Partners
IKKΓMDA5NLRP3PKN2RIG-IRIOK3RND3ROCK1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 TRIM40 physically binds to Nedd8 and promotes neddylation of IKKγ (IKBKG) via its RING domain, leading to inhibition of NF-κB activity; a dominant-negative RING-deleted mutant fails to inhibit NF-κB activity. Co-immunoprecipitation, neddylation assay, dominant-negative RING domain mutant, siRNA knockdown with NF-κB reporter assay Carcinogenesis High 21474709
2017 TRIM40 functions as an E3 ubiquitin ligase that directly binds MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination, leading to proteasomal degradation and suppression of RLR-triggered antiviral innate immune signaling. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, TRIM40 knockout mice with in vivo viral challenge Cell reports High 29117565
2021 The atypical kinase Riok3 recruits TRIM40 and interacts with it to facilitate K48- and K27-linked ubiquitination and degradation of RIG-I and MDA5, placing Riok3 upstream of TRIM40 in the negative regulation of type I IFN signaling. Co-immunoprecipitation, ubiquitination assay, Riok3 knockout (myeloid-specific) mice, in vitro and in vivo viral infection Cell reports High 34161773
2021 TRIM40 directly interacts with NLRP3 and mediates its ubiquitination via the RING domain, suppressing NLRP3 inflammasome activation; a ΔRING mutant loses this activity. Co-immunoprecipitation, ubiquitination assay, ΔRING dominant-negative mutant, siRNA knockdown in glomerular mesangial cells Molecular immunology Medium 34763147
2023 TRIM40 directly targets ROCK1 for ubiquitination and proteasomal degradation via its RING, B-box, and C-terminal domains, reducing phosphorylation of cortical actin signaling factors and impairing intestinal epithelial barrier function; Trim40-deficient mice are resistant to DSS-induced colitis. Co-immunoprecipitation, ubiquitination assay, domain deletion mutants (ΔRING, ΔB-box, ΔC-terminal), Trim40 knockout mice with DSS colitis model Nature communications High 36755029
2024 Core fucosylation of EGFR induced by HCV promotes TRIM40-mediated K48-linked ubiquitination of RIG-I, suppressing antiviral IFN-I responses via core fucosylated-EGFR-JAK1-STAT3-RIG-I signaling. Ubiquitination assay (K48-linkage specific), EGFR glycosylation mutants, FUT8 inhibitor, tissue-targeted Fut8 silencing, viral replication assay Nature communications Medium 38253527
2023 TRIM40 interacts with DAB1 and promotes its K48-linked polyubiquitination, leading to DAB1 proteasomal degradation and suppression of Reelin/DAB1/PI3K/AKT signaling and inflammation in diabetic retinopathy. Co-immunoprecipitation, double immunofluorescence, K48-ubiquitination assay, TRIM40 overexpression via AAV in STZ diabetic mouse model Biochemical and biophysical research communications Medium 37146559
2024 TRIM40 directly binds ROCK1 (confirmed by pull-down assay), ubiquitinates it to accelerate degradation, reducing c-Myc protein stability and releasing p21 transcriptional inhibition, causing G0/G1 arrest in colorectal cancer cells. Pull-down assay, co-immunoprecipitation, ubiquitination assay, protein degradation assay, in vitro and in vivo (nude mouse) proliferation assays Biochimica et biophysica acta. Molecular cell research Medium 39357549
2024 TRIM40 directly interacts with Keap1 and promotes its ubiquitin-proteasome degradation, leading to Nrf2 nuclear translocation and activation of antioxidant downstream cascades in esophageal cancer cells. Co-immunoprecipitation, ubiquitination assay, TRIM40 knockdown/overexpression, in vitro and in vivo xenograft models International immunopharmacology Medium 38901248
2025 Rnd3 facilitates recruitment and interaction with TRIM40 to promote ROCK1 ubiquitination in cardiac microvascular endothelial cells, preserving endothelial barrier integrity under diabetic conditions. Co-immunoprecipitation, ubiquitination assay, Rnd3 overexpression in diabetic mouse model Diabetes Medium 39792251
2026 TRIM40 binds PKN2 via its B-box domain and promotes K63-linked ubiquitination of PKN2 in a C29-dependent (E3 ligase activity-dependent) manner, enhancing PKN2 phosphorylation at Ser815 and activating downstream hypertrophic signaling; TRIM40 KO attenuates and TRIM40 overexpression exacerbates cardiac hypertrophy. Co-immunoprecipitation, domain mapping (B-box mutant), E3 ligase active-site mutant (C29), K63-linkage specific ubiquitination assay, TRIM40 KO and overexpression mice with Ang II/TAC hypertrophy models, pharmacological PKN2 inhibition Advanced science High 41572508
2023 TRIM40 functions as an interferon-stimulated gene (ISG) in Pteropus vampyrus (bat) cells but not human cells, and bat TRIM40 knockdown increases IFNβ and ISG expression following poly(I:C) stimulation, demonstrating species-specific immunosuppressive function against RIG-I-like receptors. siRNA knockdown, IFN stimulation assay, poly(I:C) transfection, NiV infection with viral titer measurement Viruses Low 38005825

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers. Carcinogenesis 111 21474709
2017 The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I. Cell reports 106 29117565
2021 Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation. Cell reports 45 34161773
2023 TRIM40 is a pathogenic driver of inflammatory bowel disease subverting intestinal barrier integrity. Nature communications 37 36755029
2021 TRIM40 inhibits IgA1-induced proliferation of glomerular mesangial cells by inactivating NLRP3 inflammasome through ubiquitination. Molecular immunology 28 34763147
2024 EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses. Nature communications 24 38253527
2019 Acetic acid alleviates the inflammatory response and liver injury in septic mice by increasing the expression of TRIM40. Experimental and therapeutic medicine 22 30906467
2002 Different modes of regulation of transcription and pre-mRNA processing of the structurally juxtaposed homologs, Rnf33 and Rnf35, in eggs and in pre-implantation embryos. Nucleic acids research 13 12433986
2024 TRIM40 interacts with ROCK1 directly and inhibits colorectal cancer cell proliferation through the c-Myc/p21 axis. Biochimica et biophysica acta. Molecular cell research 8 39357549
2005 Negative transcriptional modulation and silencing of the bi-exonic Rnf35 gene in the preimplantation embryo. Binding of the CCAAT-displacement protein/Cux to the untranslated exon 1 sequence. The Journal of biological chemistry 8 15994318
2005 Transcriptional modulation of the pre-implantation embryo-specific Rnf35 gene by the Y-box protein NF-Y/CBF. The Biochemical journal 7 15516209
2023 TRIM40 ameliorates diabetic retinopathy through suppressing inflammation via Reelin/DAB1 signaling disruption: A mechanism by proteasomal degradation of DAB1. Biochemical and biophysical research communications 6 37146559
2025 Rnd3 Ameliorates Diabetic Cardiac Microvascular Injury via Facilitating Trim40-Mediated Rock1 Ubiquitination. Diabetes 3 39792251
2023 Pteropus vampyrus TRIM40 Is an Interferon-Stimulated Gene That Antagonizes RIG-I-like Receptors. Viruses 3 38005825
2024 Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A. International immunopharmacology 1 38901248
2026 TRIM40 Drives Pathological Cardiac Hypertrophy and Heart Failure via Ubiquitination of PKN2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41572508