TRIM6

TRIM6 is a RING-domain E3 ubiquitin ligase that functions at the intersection of antiviral innate immunity, cell-cycle control, and cancer biology by directing substrate-specific and unanchored polyubiquitination (PMID:24882218, PMID:31992359). Its canonical role is in type I interferon (IFN-I) signaling: cooperating with the E2 conjugase UbE2K, TRIM6 synthesizes unanchored K48-linked polyubiquitin chains that activate the kinase IKKε, which it binds directly, driving IKKε oligomerization and autophosphorylation, STAT1 phosphorylation, and induction of interferon-stimulated genes (PMID:24882218, PMID:27622505). This axis is targeted by viruses for evasion—Nipah virus matrix protein triggers proteasomal degradation of TRIM6 to dampen IKKε activity (PMID:27622505), and Ebola VP35 is ubiquitinated by TRIM6 on K309 while also sequestering its unanchored chains (PMID:28679761). TRIM6 additionally restricts or supports diverse viruses through substrate ubiquitination, including K29-linked ubiquitination of SARS-CoV-2 nucleocapsid protein to enhance viral RNA binding and replication (PMID:38515377) and K27-linked ubiquitination of cGAS to suppress the cGAS-STING pathway (PMID:40817248). Beyond immunity, TRIM6 acts as a pro-proliferative and pro-tumorigenic factor by ubiquitinating and degrading antiproliferative and tumor-suppressor substrates—TIS21 in colorectal cancer (PMID:31992359), FOXO3A in glioma (PMID:38759605), TSC1/TSC2 to activate mTORC1 in renal fibrosis (PMID:33634104), SLC1A5 to suppress ferroptosis in lung cancer (PMID:36654781), and DDX58/RIG-I to promote EMT in hepatocellular carcinoma (PMID:40348925). In embryonic stem cells, TRIM6 restrains Myc transcriptional activity to maintain pluripotency (PMID:22328504).

1. 2012 Medium

   Established the first functional role of TRIM6 in a defined cellular context—restraining Myc-driven transcription to preserve stem cell identity—before its enzymatic mechanism was known.

   Evidence Co-IP of TRIM6–Myc, siRNA knockdown in ES cells with pluripotency marker and reporter readouts

   PMID:22328504

   Open questions at the time

   • Whether the Myc regulation depends on TRIM6 E3 catalytic activity was not resolved
   • No ubiquitination linkage or substrate site defined
2. 2014 High

   Defined the core enzymatic mechanism: TRIM6 partners with UbE2K to build unanchored K48-linked polyubiquitin chains that activate IKKε for STAT1-dependent IFN-I responses, distinguishing TRIM6 as a producer of non-substrate-attached chains.

   Evidence Co-IP, in vitro unanchored chain synthesis assays, siRNA knockdown with STAT1 phosphorylation and ISG readouts

   PMID:24882218

   Open questions at the time

   • Structural basis of how unanchored chains activate IKKε not resolved
   • Whether TRIM6 also generates substrate-conjugated chains in this pathway unclear
3. 2016 High

   Showed the TRIM6–IKKε axis is a viral evasion target, with Nipah virus M protein degrading TRIM6 to impair IKKε oligomerization and IFN signaling.

   Evidence Reciprocal Co-IP, confocal microscopy, IKKε oligomerization/autophosphorylation assays, recombinant NiV ΔM infection

   PMID:27622505

   Open questions at the time

   • E3 ligase mediating NiV-M-induced TRIM6 degradation not identified
   • Mechanism linking TRIM6 loss to reduced unanchored chains not fully detailed
4. 2017 High

   Demonstrated TRIM6 directly engages and ubiquitinates a viral IFN antagonist (EBOV VP35 at K309), while VP35 reciprocally counteracts TRIM6, revealing a bidirectional host–virus conflict at the ubiquitin level.

   Evidence MS-mapped ubiquitination site, Co-IP, minigenome polymerase assay, infectious EBOV in TRIM6-KO cells

   PMID:28679761

   Open questions at the time

   • Ubiquitin linkage type on VP35 not specified
   • How TRIM6 enhances EBOV polymerase activity mechanistically unclear
5. 2019 Medium

   Extended the TRIM6–IKKε–STAT1 axis to a pathological in vivo setting, showing catalytic-dependent STAT1 activation drives cardiomyocyte apoptosis and ischemia/reperfusion injury.

   Evidence Mouse MI/R model, gain/loss-of-function, E3 catalytic mutant, pharmacological IKKε/STAT1 inhibition

   PMID:31171760

   Open questions at the time

   • Upstream signals inducing TRIM6 in cardiomyocytes not defined
   • Single-lab in vivo finding
6. 2020 Medium

   Identified VAMP8 as a downstream effector of TRIM6 in the IFN-I signaling axis and showed TRIM6 restricts West Nile Virus replication.

   Evidence TRIM6-KO A549 cells, NGS to identify VAMP8, VAMP8 knockdown epistasis, JAK1/STAT1 phosphorylation and ISG readouts, WNV replication assays

   PMID:31694946

   Open questions at the time

   • Whether VAMP8 is a direct TRIM6 ubiquitination substrate not established
   • Molecular connection between TRIM6 and VAMP8 not defined
7. 2020 Medium

   Revealed TRIM6 as a pro-proliferative E3 in cancer by catalytically degrading the antiproliferative protein TIS21 (K5), linking TRIM6 to FoxM1/Cyclin B1/c-Myc-driven G2/M progression.

   Evidence Co-IP/proteomics, ubiquitination assay with C15A catalytic mutant, TIS21 rescue, in vitro/in vivo proliferation assays

   PMID:31992359

   Open questions at the time

   • Ubiquitin linkage type on TIS21 not specified
   • Single-lab finding
8. 2021 Medium

   Connected TRIM6 to mTORC1 signaling and renal fibrosis through ubiquitination of the TSC1/TSC2 tumor-suppressor complex, with TRIM6 itself induced by Angiotensin II–driven NF-κB.

   Evidence Co-IP, TSC1/2 ubiquitination assays, siRNA in HK2 cells, 5/6-nephrectomy rat model, mTORC1 pathway immunoblots

   PMID:33634104

   Open questions at the time

   • Ubiquitin linkage and modification sites on TSC1/2 not defined
   • Single-lab finding
9. 2023 Medium

   Showed TRIM6 suppresses ferroptosis by degrading the glutamine transporter SLC1A5, reducing glutaminolysis and lipid peroxidation, and lowering chemosensitivity in lung cancer.

   Evidence Co-IP, ubiquitination assay, gain/loss-of-function with ferroptosis markers, xenograft models

   PMID:36654781

   Open questions at the time

   • Ubiquitin linkage type and SLC1A5 modification sites not defined
   • Single-lab finding
10. 2024 Medium

    Demonstrated TRIM6 degrades FOXO3A to drive glioma malignancy, broadening its tumor-suppressor-degrading repertoire.

    Evidence Co-IP, FOXO3A stability immunoblots, loss/gain-of-function phenotypic assays, rescue, xenograft

    PMID:38759605

    Open questions at the time

    • Ubiquitin linkage and FOXO3A sites not defined
    • Single-lab finding
11. 2024 High

    Resolved a domain-specific, linkage-specific viral mechanism—TRIM6 catalyzes K29-linked ubiquitination of SARS-CoV-2 NP (K102/K347/K361) via its RING and B-box-CCD domains to enhance NP–RNA binding and viral replication.

    Evidence Domain-mapped Co-IP, MS-identified sites with mutation, trVLP reverse genetics, TRIM6-KO replication and RNA-binding assays

    PMID:38515377

    Open questions at the time

    • Whether K29 chains alter NP function in authentic SARS-CoV-2 infection not fully tested
    • Generalizability across coronaviruses beyond SARS-CoV inferred
12. 2024 Medium

    Showed TRIM6 degrades GPX3 via K48-linked ubiquitination, linking it to mitochondrial ROS, NLRP3 inflammasome activation, and pyroptosis in renal tubular cells.

    Evidence Co-IP, ubiquitination assay, gain/loss-of-function, ROS flow cytometry, pyroptosis marker readouts

    PMID:38420829

    Open questions at the time

    • GPX3 ubiquitination sites not mapped
    • Single-lab finding
13. 2025 Medium

    Established a STAT3→TRIM6→DDX58→Snail1 axis in which TRIM6 is transcriptionally induced by STAT3 and degrades DDX58/RIG-I to promote EMT and HCC invasion.

    Evidence ChIP (STAT3–TRIM6 promoter), Co-IP (TRIM6–DDX58), ubiquitination assay, invasion assays, pathway immunoblots

    PMID:40348925

    Open questions at the time

    • DDX58 ubiquitin linkage and sites not defined
    • Single-lab finding
14. 2025 Medium

    Showed TRIM6 catalyzes K27-linked ubiquitination of cGAS to suppress cGAS-STING immunity, and that its ablation enhances anti-tumor immunity and anti-PD-L1 efficacy in MSS gastric cancer.

    Evidence TRIM6-KO murine models, K27-linkage ubiquitination assays, cGAS-STING immunoblots, TIL flow cytometry, RNA-seq

    PMID:40817248

    Open questions at the time

    • cGAS modification sites not mapped
    • Single-lab finding

• How TRIM6 selects among distinct ubiquitin linkage types (K27, K29, K48, unanchored) for different substrates, and what determines context-specific antiviral-restrictive versus pro-viral and pro-tumorigenic outcomes, remains unresolved.
• No structural model explaining linkage specificity
• No unified regulatory logic linking substrate choice to cellular context
• Most non-immune substrate findings rest on single-lab studies