Affinage

TRIM40

E3 ubiquitin ligase TRIM40 · UniProt Q6P9F5

Length
258 aa
Mass
29.3 kDa
Annotated
2026-06-10
13 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM40 is a RING-domain E3 ubiquitin ligase that functions as a broad negative regulator of innate immune, inflammatory, and cytoskeletal signaling by ubiquitinating distinct substrates in a domain-dependent manner (PMID:21474709, PMID:29117565, PMID:36755029). In antiviral immunity it binds the RNA sensors RIG-I and MDA5 and catalyzes K27- and K48-linked polyubiquitination that targets them for proteasomal degradation, dampening RLR-triggered type I interferon responses (PMID:29117565); this degradation is potentiated by partner proteins, with the atypical kinase Riok3 recruiting TRIM40 to the sensors (PMID:34161773) and a FUT8/EGFR–JAK1–STAT3 axis enhancing K48-linked ubiquitination of RIG-I during infection (PMID:38253527). TRIM40 likewise restrains NF-κB signaling by promoting RING-dependent neddylation of IKKγ/NEMO (PMID:21474709) and suppresses NLRP3 inflammasome activation through NLRP3 ubiquitination (PMID:34763147). Beyond immunity, TRIM40 controls cytoskeletal and proliferative signaling by directing the ubiquitination and proteasomal degradation of ROCK1—requiring its RING, B-box, and C-terminal domains and facilitated by the recruiting partner Rnd3—thereby preserving epithelial and endothelial barrier integrity and imposing cell-cycle arrest via the c-Myc/p21 axis (PMID:36755029, PMID:39357549, PMID:39792251). It further degrades DAB1 and Keap1 to modulate Reelin/PI3K-AKT and Nrf2 antioxidant signaling (PMID:37146559, PMID:38901248), and uses a B-box-dependent, C29-requiring activity to K63-ubiquitinate and activate PKN2 in cardiac hypertrophy, showing that its outputs span both degradative and non-degradative ubiquitin linkages (PMID:41572508).

Mechanistic history

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

    Established TRIM40 as a RING-dependent suppressor of NF-κB, the first mechanistic link between this ligase and inflammatory signaling, acting through an unusual neddylation rather than canonical ubiquitination.

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

    PMID:21474709

    Open questions at the time
    • Did not define the structural basis for Nedd8 versus ubiquitin selectivity
    • Physiological context of NEMO neddylation not addressed in vivo
  2. 2017 High

    Defined TRIM40 as a brake on antiviral innate immunity by showing it ubiquitinates and degrades the RNA sensors RIG-I and MDA5, extending its negative-regulatory role from NF-κB to the RLR/IFN axis.

    Evidence Reciprocal Co-IP, K27/K48-linkage-specific ubiquitination assays, proteasome inhibition, and TRIM40-deficient mice with viral challenge

    PMID:29117565

    Open questions at the time
    • Did not resolve how K27 versus K48 linkages partition functionally
    • Recruitment to sensors not yet explained
  3. 2021 High

    Identified Riok3 as a recruiting partner that bridges TRIM40 to RIG-I/MDA5, answering how the ligase is targeted to its antiviral substrates.

    Evidence Co-IP, ubiquitination assay, Riok3 knockout mice, and viral replication assays

    PMID:34161773

    Open questions at the time
    • Whether Riok3 kinase activity is required for recruitment unclear
    • Does not address TRIM40 regulation in non-immune tissues
  4. 2021 Medium

    Extended TRIM40's anti-inflammatory role to the NLRP3 inflammasome, showing RING-dependent NLRP3 ubiquitination limits mesangial cell proliferation.

    Evidence Co-IP, ubiquitination assay, ΔRING mutant, siRNA knockdown, and proliferation assay

    PMID:34763147

    Open questions at the time
    • Ubiquitin linkage type on NLRP3 not specified
    • No in vivo genetic confirmation
  5. 2023 High

    Demonstrated a cytoskeletal function distinct from immunity by showing multidomain-dependent ROCK1 degradation maintains cortical actin and epithelial barrier integrity, with loss driving IBD-like pathology.

    Evidence Co-IP, ubiquitination assay, ΔRING/ΔB-box/ΔC-terminal mutants, and Trim40 knockout mice in DSS colitis

    PMID:36755029

    Open questions at the time
    • ROCK1 ubiquitin linkage type not defined
    • How multiple domains coordinate substrate engagement unresolved
  6. 2023 Medium

    Showed TRIM40 degrades DAB1 to suppress Reelin/PI3K-AKT signaling, broadening its substrate repertoire into neurodevelopmental/inflammatory signaling relevant to diabetic retinopathy.

    Evidence Co-IP, immunofluorescence, K48-linked ubiquitination assay, and AAV TRIM40 overexpression in diabetic mice

    PMID:37146559

    Open questions at the time
    • Loss-of-function genetics not tested
    • Direct versus indirect DAB1 binding not fully resolved
  7. 2023 Medium

    Revealed species-specific deployment of TRIM40 as an interferon-stimulated gene in fruit bats that antagonizes RLR signaling, a regulatory wiring not seen in human cells.

    Evidence siRNA knockdown, poly(I:C) stimulation, RT-qPCR of IFNβ/ISGs, and NiV infection in bat cells

    PMID:38005825

    Open questions at the time
    • Mechanistic basis of bat-specific ISG induction unknown
    • Substrate engagement in bat cells not biochemically mapped
  8. 2024 Medium

    Placed TRIM40 downstream of a virus-induced FUT8/EGFR/JAK1-STAT3 axis that enhances RIG-I ubiquitination, connecting glycosylation signaling to TRIM40-mediated IFN suppression.

    Evidence Co-IP, K48-linkage ubiquitination assay, FUT8 inhibitor, EGFR glycosite mutant, and Fut8 siRNA with viral replication assay

    PMID:38253527

    Open questions at the time
    • How STAT3 signaling mechanistically boosts TRIM40 activity unclear
    • TRIM40 abundance versus activity contribution not separated
  9. 2024 Medium

    Linked ROCK1 degradation to cell-cycle control, showing TRIM40 destabilizes c-Myc and de-represses p21 to enforce G0/G1 arrest in colorectal cancer.

    Evidence Direct pull-down, Co-IP, ubiquitination and degradation assays, and in vitro/in vivo proliferation assays

    PMID:39357549

    Open questions at the time
    • Direct versus ROCK1-dependent control of c-Myc not fully separated
    • Context-dependence across tumor types untested
  10. 2024 Medium

    Identified Keap1 as a substrate, positioning TRIM40 as an activator of Nrf2 antioxidant signaling through Keap1 degradation in esophageal cancer.

    Evidence Co-IP, ubiquitination assay, TRIM40 deletion/overexpression, and xenograft

    PMID:38901248

    Open questions at the time
    • Ubiquitin linkage type and direct binding region undefined
    • Single study without independent replication
  11. 2025 Medium

    Generalized the recruiting-partner model to the cytoskeletal arm by showing Rnd3 bridges TRIM40 to ROCK1 to preserve endothelial barrier integrity in the diabetic heart.

    Evidence Co-IP, ubiquitination assay, Rnd3 overexpression in cardiac microvascular endothelial cells, and diabetic cardiomyopathy model

    PMID:39792251

    Open questions at the time
    • Rnd3 versus other adaptors specificity not addressed
    • No loss-of-function genetics for Rnd3 in this context
  12. 2026 High

    Showed TRIM40 can activate rather than degrade a substrate, using B-box-dependent binding and C29-dependent K63-linked ubiquitination to promote PKN2 phosphorylation and cardiac hypertrophy signaling.

    Evidence Co-IP, K63-linkage ubiquitination assay, domain mutagenesis, multiple cardiac in vivo genetic models, and pharmacological PKN2 inhibition

    PMID:41572508

    Open questions at the time
    • How linkage choice (K63 versus K48) is determined across substrates unknown
    • Structural basis for B-box-mediated substrate selection not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what governs TRIM40's choice of ubiquitin linkage and degradative versus non-degradative outcomes across its many substrates, and whether a unifying structural logic dictates substrate and adaptor selection.
  • No structural model of TRIM40–substrate complexes
  • Determinants of K27/K48/K63 linkage selection unmapped
  • Adaptor specificity (Riok3 vs Rnd3) mechanism unexplained

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 3
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4
Partners
DAB1IFIH1KEAP1NLRP3PKN2RIGIRIOK3ROCK1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 TRIM40 physically binds Nedd8 and promotes neddylation of IKKγ (NEMO/inhibitor of NF-κB kinase subunit gamma) via its RING domain, leading to inhibition of NF-κB activity; a dominant-negative RING-deleted mutant loses this activity. Co-immunoprecipitation, neddylation assay, dominant-negative RING-domain mutant, siRNA knockdown with NF-κB reporter assay Carcinogenesis High 21474709
2017 TRIM40 acts as an E3 ubiquitin ligase that directly binds MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination, targeting them for proteasomal degradation and thereby suppressing RLR-triggered antiviral innate immune signaling. Co-immunoprecipitation, ubiquitination assay (K27- and K48-linkage-specific), proteasome inhibitor experiments, TRIM40-deficient mice, in vivo viral challenge Cell reports High 29117565
2021 Riok3 (an atypical kinase) recruits TRIM40 and interacts with it to facilitate TRIM40-mediated K48- and K27-linked ubiquitination of RIG-I and MDA5, promoting their degradation and negatively regulating type I IFN signaling. Co-immunoprecipitation, ubiquitination assay, Riok3 knockout mice, in vitro viral replication assay Cell reports High 34161773
2021 TRIM40 binds NLRP3 and promotes its ubiquitination (E3 ligase activity required via RING domain), suppressing NLRP3 inflammasome activation and IgA1-induced glomerular mesangial cell proliferation; RING-deleted TRIM40 loses these effects. Co-immunoprecipitation, ubiquitination assay, dominant-negative RING-domain mutant (ΔRING), siRNA knockdown, cell proliferation assay Molecular immunology Medium 34763147
2023 TRIM40 directly targets ROCK1 for ubiquitination and proteasomal degradation via its RING, B-box, and C-terminal domains; loss of any of these domains impairs ROCK1 degradation, leading to cortical actin disruption and epithelial barrier failure in IBD. Co-immunoprecipitation, ubiquitination assay, domain-deletion mutants (ΔRING, ΔB-box, ΔC-terminal), Trim40 knockout mice (DSS-induced colitis model), barrier function assay Nature communications High 36755029
2024 Virus-induced FUT8 upregulation promotes core fucosylation of EGFR, which activates a JAK1-STAT3 signaling axis that enhances TRIM40-mediated K48-linked ubiquitination of RIG-I, suppressing IFN-I antiviral responses. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), FUT8 inhibitor (2FF), glycosylation site-specific EGFR mutation (Q352AT), tissue-targeted Fut8 siRNA knockdown, viral replication assay Nature communications Medium 38253527
2023 TRIM40 directly interacts with DAB1 and promotes its K48-linked polyubiquitination and proteasomal degradation, disrupting Reelin/DAB1 signaling and reducing downstream PI3K/AKT activation and inflammatory responses in diabetic retinopathy. Co-immunoprecipitation, double immunofluorescence, K48-linked ubiquitination assay, AAV-mediated TRIM40 overexpression in STZ-induced diabetic mice Biochemical and biophysical research communications Medium 37146559
2024 TRIM40 directly binds ROCK1 and promotes its ubiquitination and degradation, reducing c-Myc protein stability and releasing p21 transcriptional repression, causing G0/G1 cell cycle arrest in colorectal cancer cells. Pull-down assay (direct binding), Co-immunoprecipitation, ubiquitination assay, protein degradation assay, in vitro and in vivo 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 deletion and overexpression, in vivo xenograft International immunopharmacology Medium 38901248
2025 Rnd3 facilitates the recruitment and interaction of Trim40 with Rock1 to promote Rock1 ubiquitination, preserving endothelial barrier integrity in the diabetic heart. Co-immunoprecipitation, ubiquitination assay, Rnd3 overexpression in cardiac microvascular endothelial cells, in vivo diabetic cardiomyopathy model Diabetes Medium 39792251
2026 TRIM40 binds PKN2 via its B-box domain and promotes K63-linked ubiquitination of PKN2 in a manner requiring C29-dependent E3 ligase activity, leading to enhanced PKN2 phosphorylation at Ser815 and activation of downstream cardiac hypertrophy signaling. Co-immunoprecipitation, K63-linkage-specific ubiquitination assay, TRIM40 KO and cardiac-specific knockdown/overexpression mice, pharmacological PKN2 inhibition, TAC/Ang II hypertrophy models Advanced science High 41572508
2023 In pteropodid (fruit bat) cells, TRIM40 is an interferon-stimulated gene (ISG) that, when knocked down, increases IFNβ and ISG expression following poly(I:C) stimulation, indicating bat TRIM40 antagonizes RIG-I-like receptor signaling as an ISG (not observed in human cells). siRNA knockdown, poly(I:C) transfection, RT-qPCR for IFNβ and ISGs, NiV infection model in bat cells Viruses Medium 38005825

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers. Carcinogenesis 112 21474709
2017 The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I. Cell reports 108 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 39 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 27 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
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 9 39357549
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
2023 Pteropus vampyrus TRIM40 Is an Interferon-Stimulated Gene That Antagonizes RIG-I-like Receptors. Viruses 4 38005825
2025 Rnd3 Ameliorates Diabetic Cardiac Microvascular Injury via Facilitating Trim40-Mediated Rock1 Ubiquitination. Diabetes 3 39792251
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

Missed literature

Know a paper Affinage missed for TRIM40? Flag it for the maintainers and the community.

No submissions yet.