Affinage

TRIM21

E3 ubiquitin-protein ligase TRIM21 · UniProt P19474

Length
475 aa
Mass
54.2 kDa
Annotated
2026-06-10
100 papers in source corpus 48 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM21 is a cytosolic RING-domain E3 ubiquitin ligase that doubles as a high-affinity intracellular Fc receptor, coupling antibody-mediated pathogen recognition to proteasomal destruction and innate immune activation (PMID:28049840, PMID:36996217, PMID:33258165, PMID:39455551). As an effector of antibody-dependent intracellular neutralization, it intercepts antibody-coated viral and pathological protein targets entering the cytosol—including tau seeds, viral nucleoproteins, and adenoviral vectors—routing them for degradation through the proteasome and the AAA-ATPase p97/VCP while inducing innate/intrinsic immune gene programs (PMID:28049840, PMID:36996217, PMID:30209217, PMID:33258165, PMID:39455551). Mechanistically, productive degradation requires ubiquitination of the target protein itself rather than TRIM21 self-ubiquitination, and substrate clustering or multimerization activates the ligase—a principle exploited by Trim-Away, PROTAC, and molecular-glue degraders that recruit TRIM21 to substrates such as nuclear pore proteins (PMID:39488207, PMID:36807144, PMID:40247740). Beyond antiviral defense, TRIM21 ubiquitinates a broad substrate repertoire using distinct chain linkages with opposing fates: K48-linked chains drive proteasomal degradation of substrates including SAMHD1, VDAC2, METTL3, mutant p53, and lipogenic regulators (SREBF1, ChREBP, FASN) (PMID:31797533, PMID:36797289, PMID:36749630, PMID:40175350, PMID:37937648, PMID:36694250), whereas K63-linked chains modify p62/SQSTM1, G3BP1, CLASPIN, FSP1, PD-1, and others to alter their oligomerization, localization, or stability without necessarily destroying them (PMID:26942676, PMID:36692217, PMID:35048968, PMID:37587773, PMID:39905727). Through these substrates TRIM21 governs redox homeostasis via p62/Keap1-Nrf2 (PMID:26942676, PMID:39172027), stress-granule phase separation (PMID:36692217), the replication-checkpoint and DNA damage response (PMID:35048968), ferroptosis through GPX4, FSP1, and METTL3 (PMID:37587773, PMID:36958437, PMID:40175350), pyroptosis via GSDMD (PMID:34511601), metabolic flux (pentose phosphate pathway, lipogenesis) (PMID:32312982, PMID:37937648), and immune-checkpoint and tumor immune evasion through PD-1 and CD47 (PMID:39905727, PMID:37541303). TRIM21's own activity is tuned by post-translational regulation: neddylation by UBE2M at K129/K134 (PMID:37343564), acetylation at K351 (PMID:35770730), ERK2 phosphorylation at T396 (PMID:39388269), oxidation-induced disulfide oligomerization at C92/C111/C114 (PMID:39172027), and deubiquitination/stabilization by USP28 (PMID:39431010).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2016 High

    Established that beyond immunity TRIM21 controls redox homeostasis by K63-ubiquitinating p62/SQSTM1, defining a direct cellular substrate and an antioxidant-suppressing function.

    Evidence Co-IP, K7 site mutagenesis, in vitro ubiquitination, and Trim21-knockout mouse injury models

    PMID:26942676

    Open questions at the time
    • Did not resolve how oxidative state feeds back onto TRIM21 activity
    • Linkage of p62 modification to broader Nrf2 dynamics not fully mapped
  2. 2017 High

    Defined TRIM21 as a cytosolic Fc receptor capable of neutralizing antibody-bound pathological protein seeds (tau), extending intracellular antibody immunity beyond intact pathogens.

    Evidence Fluorescent seeding assays with TRIM21 manipulation and proteasome/p97 inhibition

    PMID:28049840 PMID:36996217

    Open questions at the time
    • Did not establish whether tau is directly ubiquitinated by TRIM21
    • Role of p97/VCP versus proteasome in seed disassembly not separated
  3. 2018 High

    Demonstrated in vivo that TRIM21 enforces antibody-dependent blockade of viral gene delivery and drives broad innate immune transcription, linking the Fc-receptor function to organismal antiviral defense.

    Evidence TRIM21 knockout mice, antibody point mutant, and transcriptomics of transduced tissue

    PMID:30209217

    Open questions at the time
    • Direct degradation substrate within the adenoviral particle not defined
    • Mechanism connecting degradation to immune gene induction unresolved
  4. 2020 High

    Showed TRIM21-mediated antigen degradation can prime cytotoxic T cells (ADIN) and that TRIM21 degrades antiviral and metabolic substrates, broadening its functions to T-cell immunity and metabolism.

    Evidence TRIM21 KO mice with LCMV/CTL assays, plus KO/OE ubiquitination studies of SAMHD1, G6PD, and HBV Pol

    PMID:31797533 PMID:32245233 PMID:32312982 PMID:33258165

    Open questions at the time
    • How antigen routing to MHC-I presentation is coordinated with degradation not resolved
    • PI3K/AKT regulation of TRIM21 toward G6PD only partially mapped
  5. 2022 High

    Revealed that TRIM21 uses linkage-specific ubiquitination (K63 on CLASPIN, K27 on ERK1/2) to regulate the replication checkpoint and kinase signaling rather than simply degrade substrates.

    Evidence Co-IP, linkage-specific ubiquitination assays, catalytic-mutant controls, and replication-fork/CHK1 and ERK signaling readouts

    PMID:35048968 PMID:39533840

    Open questions at the time
    • Structural basis for chain-linkage selection unknown
    • Context determining degradative versus non-degradative outcome not defined
  6. 2023 High

    Cell-free reconstitution proved that target-protein ubiquitination, not TRIM21 self-ubiquitination, is the obligatory step for substrate proteolysis, correcting the prior mechanistic model.

    Evidence Xenopus egg extract Trim-Away with chemical methylation of TRIM21 and target lysine-deletion mutagenesis

    PMID:36807144

    Open questions at the time
    • Whether self-ubiquitination contributes to activation upstream of target modification not fully excluded
    • E2 enzyme selectivity in extract not defined
  7. 2023 High

    Mapped TRIM21 as a hub of cell-death and redox decisions through K63/K48 modification of G3BP1, FSP1, GPX4, METTL3, VDAC2, and oxidation-sensing of its own activity.

    Evidence Co-IP, site-specific ubiquitination assays, in vitro LLPS reconstitution, membrane fractionation, and Cys-to-Ser oxidation mutagenesis with KO models

    PMID:36692217 PMID:36797289 PMID:36958437 PMID:37587773 PMID:39172027 PMID:40175350

    Open questions at the time
    • Tissue/context determinants directing pro- versus anti-ferroptotic outcomes unresolved
    • How oxidation-induced oligomerization is reversed in cells not defined
  8. 2023 High

    Identified upstream regulators (UBE2M neddylation at K129/134, SIRT5-dependent K351 acetylation, USP28 stabilization) that tune TRIM21 ligase output in inflammation and cardiac stress.

    Evidence Site-specific neddylation/acetylation mutagenesis, deubiquitination assays, and macrophage- or cardiomyocyte-specific KO mouse models

    PMID:35770730 PMID:37343564 PMID:39431010

    Open questions at the time
    • Crosstalk hierarchy among the multiple PTMs is unknown
    • Whether modifications alter substrate selectivity versus global activity unresolved
  9. 2024 High

    Established TRIM21 as a tractable degradation effector whose dependence on substrate clustering enables molecular glues and PROTACs, validated structurally against nuclear pore proteins.

    Evidence DEL/molecular-glue screens, crystallography of TRIM21-NUP98 and TRIM21-ligand interfaces, proteomics, and KO controls

    PMID:39488207 PMID:40247740

    Open questions at the time
    • Generalizability of clustering requirement across non-condensate substrates not fully defined
    • Endogenous physiological glue-like activators unknown
  10. 2024 High

    Extended TRIM21 into immune-checkpoint and tumor immune-evasion control via K63-stabilization of PD-1 and degradation of CD47, with ERK2 T396 phosphorylation gating substrate engagement.

    Evidence Site/linkage-specific ubiquitination mutagenesis, knock-in alleles, Trim21 KO mice, and tumor immunotherapy models

    PMID:37541303 PMID:39388269 PMID:39905727

    Open questions at the time
    • Why some substrates are stabilized (K63) while structurally similar ones are degraded not mechanistically explained
    • Therapeutic window of TRIM21 modulation in immunity untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what determines TRIM21's choice of ubiquitin chain linkage and degradative versus non-degradative substrate fate across its very broad substrate set.
  • No unifying structural model for linkage selection
  • Substrate-selectivity rules across tissues undefined
  • Interplay of the multiple regulatory PTMs in vivo unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 8 GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 5 GO:0001618 virus receptor activity 3
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
CLASPINERK1/2FSP1G3BP1GSDMDPD-1SQSTM1VDAC2

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 TRIM21 directly interacts with SQSTM1/p62 and ubiquitylates p62 at lysine 7 (K7) via K63-linked ubiquitin chains, which abrogates p62 oligomerization and sequestration of client proteins (including Keap1), thereby suppressing the antioxidant response. TRIM21-deficient cells display enhanced antioxidant response and reduced cell death under oxidative stress. Co-IP, ubiquitination assay, mutagenesis (K7 site), genetic ablation in mice (liver insult and pressure overload models) Molecular cell High 26942676
2017 TRIM21 acts as a cytosolic Fc receptor that detects antibody-coated tau seeds entering the cell; after binding, TRIM21 neutralizes tau seeds through the proteasome and AAA ATPase p97/VCP, inhibiting pathological tau aggregate formation. Fluorescent morphology-based seeding assays, TRIM21 knockdown/overexpression, pharmacological inhibition of proteasome and p97/VCP Proceedings of the National Academy of Sciences of the United States of America High 28049840 36996217
2019 TRIM21 interacts with SAMHD1 and promotes its K48-linked ubiquitination and proteasomal degradation, thereby reducing SAMHD1-dependent restriction of EV71 and HIV-1 replication. The SPRY domain of TRIM21 is required for SAMHD1 binding and K622 of SAMHD1 is the ubiquitination site. Co-IP, in vitro ubiquitination assay, domain-deletion mutants, neonatal mouse model EMBO reports High 31797533
2018 TRIM21 mediates antibody-dependent inhibition of adenoviral gene delivery in vivo; genetic KO of TRIM21 or a single antibody point mutation restores transgene expression. TRIM21 is also responsible for blocking cytotoxic T cell induction by adenoviral vaccine vectors and for upregulating hundreds of innate/intrinsic immune genes in vector-transduced tissue. TRIM21 genetic knockout mice, antibody point mutant, transcriptomic analysis of transduced tissue, viral challenge models Proceedings of the National Academy of Sciences of the United States of America High 30209217
2020 TRIM21 functions as an E3 ubiquitin ligase targeting G6PD for degradation, thereby negatively regulating the pentose phosphate pathway (PPP). PI3K/AKT activation inhibits TRIM21 to stabilize G6PD and promote PPP flux. Knockout of TRIM21 promotes PPP activity and cell proliferation. TRIM21 knockout/overexpression, ubiquitination assays, PTEN-null cancer cell models and murine in vivo models Nature communications Medium 32312982
2020 TRIM21 uses anti-nucleoprotein (N) antibodies to target viral N protein for cytosolic degradation and generate cytotoxic T cells against N peptide, providing T cell-mediated viral clearance via antibody-dependent intracellular neutralization (ADIN) in LCMV infection. TRIM21 KO mice, LCMV infection model, CTL assays, antibody transfer experiments The EMBO journal High 33258165
2021 TRIM21 interacts with GSDMD via its PRY-SPRY domain, maintaining GSDMD stable expression in resting cells and inducing GSDMD-N terminus aggregation during pyroptosis, thereby acting as a positive regulator of GSDMD-dependent pyroptosis. TRIM21-deficient cells show reduced pyroptosis in response to NLRP3 or NLRC4 inflammasome activation, and TRIM21 KO mice are protected from LPS-induced inflammation and DSS-induced colitis. Co-IP (PRY-SPRY domain mapping), TRIM21 KO cells and mice, inflammasome activation assays, colitis model Cell death and differentiation High 34511601
2023 TRIM21 promotes K48-linked ubiquitination and proteasomal degradation of VDAC2, inhibiting VDAC2 oligomer pore formation and thereby blocking mitochondrial DNA release and cGAS/STING pathway activation following irradiation in nasopharyngeal carcinoma cells. TRIM21 KO, Co-IP, ubiquitination assay, mitochondrial DNA release assay, cGAS/STING pathway readouts, in vivo tumor models Nature communications High 36797289
2023 TRIM21 catalyzes K63-linked ubiquitination of the stress granule core protein G3BP1, which effectively inhibits G3BP1 liquid-liquid phase separation (LLPS) and stress granule formation in vitro and in cells. E3 ligase screen in SGs, Co-IP, in vitro LLPS assay, TRIM21 knockdown/overexpression, ubiquitination assay Autophagy High 36692217
2023 UBE2M (E2 enzyme) neddylates TRIM21 at K129/K134; this neddylation promotes TRIM21-mediated K48-linked ubiquitination and degradation of VHL, which prevents VHL-dependent degradation of HIF-1α and sustains IL-1β production in macrophages during obesity-induced inflammation. UBE2M KO macrophage mice, neddylation assay, Co-IP, ubiquitination assay, HFD mouse models Cell metabolism High 37343564
2022 TRIM21 directly interacts with and ubiquitinates CLASPIN via K63-linked chains, which counteracts the K6-linked ubiquitination of CLASPIN essential for its interaction with TIPIN and chromatin loading. Overexpression of TRIM21 (but not a catalytically inactive mutant) compromises CHK1 activation, leading to replication fork instability. Co-IP, ubiquitination assay, catalytically inactive TRIM21 mutant, CHK1 activation assays, replication fork assays Nucleic acids research High 35048968
2023 TRIM21 identified as an E3 ubiquitin ligase for mutant p53 (mutp53); it directly interacts with mutp53 but not wild-type p53, promoting mutp53 ubiquitination and proteasomal degradation to suppress mutp53 gain-of-function in tumorigenesis. TRIM21 deletion in p53R172H knockin mice caused mutp53 accumulation in normal tissues and earlier tumor onset. mutp53-interacting protein screen, Co-IP, ubiquitination assay, TRIM21 KO in p53R172H knockin mice The Journal of clinical investigation High 36749630
2023 TRIM21 mediates K63-linked ubiquitination of FSP1 at K322 and K366 residues, which is essential for FSP1 plasma membrane translocation and its ferroptosis suppression activity. Co-IP, ubiquitination assay with site-directed mutagenesis (K322R, K366R), membrane fractionation, RSL3-induced ferroptosis assays, subcutaneous tumor model Advanced science High 37587773
2023 TRIM21 ubiquitylates GPX4, promoting its degradation, and thereby promotes ferroptosis in ischemia/reperfusion-induced acute kidney injury. TRIM21 KO mice are protected from I/R-AKI with upregulated GPX4. Co-IP, ubiquitination assay, Trim21-/- mice I/R model, H/R cell model, ferroptosis markers Life sciences Medium 36958437
2023 TRIM21 directly interacts with SARS-CoV-2 nucleocapsid (N) protein and ubiquitinates it at K375, leading to proteasomal degradation. This ubiquitination was also observed for N proteins of SARS-CoV-2 variants and related coronaviruses. Immunoprecipitation/mass spectrometry, Co-IP, ubiquitination assay, proteasome inhibitor experiments Journal of medical virology Medium 37185839
2020 TRIM21 interacts with the TP domain of HBV DNA polymerase (Pol) via its SPRY domain and promotes ubiquitination at K260 and K283 of HBV Pol using its RING domain, leading to proteasomal degradation and restriction of HBV DNA replication. FLAG affinity purification/mass spectrometry, Co-IP, ubiquitination assay, domain deletion mutants, HBV replication assays Viruses Medium 32245233
2022 TRIM21 promotes K48-linked ubiquitination of IRF7, leading to its degradation, to promote rabies virus (RABV) replication via the IRF7-IFN axis; TRIM21 knockdown inhibits RABV replication while overexpression promotes it. TRIM21 knockdown/overexpression, Co-IP, ubiquitination assay, IFN production assays, RABV replication assays International journal of molecular sciences Medium 37446070
2022 TRIM21 directly interacts with STAT1 and acts as its E3 ubiquitin ligase, promoting STAT1 ubiquitination and degradation. TGM2 (in a GTP-binding-dependent manner) facilitates dissociation of TRIM21 from STAT1, thereby stabilizing STAT1 and promoting gastric cancer progression. Co-IP, mass spectrometry, ubiquitination assay, TGM2 mutagenesis, TGM2-STAT1-TRIM21 interaction studies Cancer communications Medium 36353796
2022 LPS challenge promotes the interaction between TRIM21 and SIRT5, leading to TRIM21-mediated SIRT5 ubiquitination and degradation. SIRT5 degradation sustains acetylation of TRIM21 at K351, increasing its E3 ligase activity in LPS-activated macrophages and enhancing IL-1β production. Co-IP, ubiquitination assay, deubiquitinase (HAUSP) competition assay, K351 acetylation mapping, IL-1β ELISA, DSS colitis model EMBO reports High 35770730
2023 Mtb infection promotes TRIM21-mediated proteasomal degradation of HERC2 (an E3 ligase of NCOA4), via p38/AKT1 signaling, which stabilizes NCOA4 and enhances NCOA4-mediated ferritin degradation (ferritinophagy), increasing iron bioavailability for intracellular Mtb growth. Co-IP, ubiquitination assay, NCOA4 KO myeloid mice, HERC2 degradation assays, Mtb infection models The Journal of clinical investigation Medium 37066876
2023 TRIM21 directly interacts with and ubiquitinates MST2 at K473 via K63-linked chains, enabling MST2 homodimer formation and enhanced MST2 kinase activity, ultimately inactivating YAP and inhibiting EMT in colorectal cancer. Co-IP, ubiquitination assay with site mutagenesis, MST2 kinase activity assay, YAP phosphorylation readout, mouse CRC models and organoids Cell chemical biology High 37354905
2023 TRIM21 promotes K48-linked ubiquitination of METTL3 at K459, leading to its proteasomal degradation, thereby promoting ferroptosis by preventing SLC7A11 mRNA stabilization in pancreatic cancer. Co-IP, ubiquitination assay with site mutagenesis (K459), ferroptosis assays, in vivo pancreatic cancer models Cell death & disease Medium 40175350
2023 TRIM21 interacts with and ubiquitinates SQSTM1/p62 at K7 via K63 linkage, abolishing TBK1-mediated phosphorylation of p62 at S403 and preventing p62 aggregation. TRIM21 is oxidized at C92, C111, C114 to form disulfide bonds causing oligomerization and reduced E3 activity, which in turn allows S403 phosphorylation and p62-mediated antioxidant sequestration. Co-IP, ubiquitination assay, phosphorylation assay, Cys-to-Ser mutagenesis, in vitro dimerization assay, PA-treated MEF and mouse models Autophagy High 39172027
2023 TRIM21 ubiquitinates ChREBP, SREBP1, ACC1, FASN, and A1CF (key lipogenesis and fructose metabolism regulators) via ubiquitin-mediated proteasomal degradation, limiting de novo lipogenesis in NASH. TRIM21 expression is induced by TNF-α plus fatty acids synergistically. Co-IP, ubiquitination assay, TRIM21 KO/OE in primary hepatocytes and mice, metabolic phenotyping JCI insight Medium 37937648
2024 TRIM21 directly interacts with c-Myc and ubiquitinates it at K148 via K63-linked chains, enabling c-Myc targeting to the autophagy machinery for degradation. ERK2 (downstream of mutant KRAS) phosphorylates TRIM21 at T396, disrupting the TRIM21-c-Myc interaction and preventing c-Myc autophagic degradation. Co-IP, ubiquitination assay (K63, K148 site mutagenesis), ERK2 phosphorylation assay (T396), autophagy flux assays, KRAS-mutant CRC models Proceedings of the National Academy of Sciences of the United States of America High 39388269
2024 (S)-ACE-OH acts as a molecular glue to induce TRIM21-NUP98 interaction, leading to ubiquitin-proteasome-dependent degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. TRIM21-based PROTACs enable selective degradation of multimeric/condensate proteins, consistent with a requirement for substrate clustering for TRIM21 activation. Co-IP, crystallography (TRIM21-NUP98 interface), proteomic studies, proteasome inhibitor experiments, TRIM21 KO validation Cell High 39488207
2023 TRIM21-dependent target protein ubiquitination (not TRIM21 self-ubiquitination) is required for Trim-Away degradation, as demonstrated in Xenopus egg cell-free extracts; chemical methylation of TRIM21 had no effect on target proteolysis, whereas deletion of all lysines in target protein abolished ubiquitination and proteasomal degradation. Cell-free Xenopus egg extract system, chemical methylation of TRIM21, target protein lysine-deletion mutagenesis, proteasomal degradation assays Cell reports High 36807144
2022 TRIM21 promotes K63-linked ubiquitination of ISG12a and facilitates its translocation into mitochondria, causing caspase 3 activation; caspase 3 then cleaves GSDME specifically during viral infection, releasing GSDME N-terminal domain and causing pyroptosis. Co-IP, ubiquitination assay, mitochondrial fractionation, caspase 3 activation assay, GSDME cleavage assay, viral infection model Journal of immunology Medium 36426955
2023 TRIM21 interacts with EPHX1 through its SPRY domain and promotes K33- and K48-linked ubiquitination at K105 of EPHX1, leading to its degradation and inhibition of arachidonic acid metabolism in pancreatic cancer. Proteomics, ubiquitomics, LC-MS/MS, Co-IP, SPRY domain mapping, ubiquitination assay with site mutagenesis Advanced science Medium 39739616
2023 TRIM21 interacts with and promotes K48-linked ubiquitination-dependent degradation of NCL (nucleolin) at K239, suppressing HCC metastasis; circ0006646 prevents NCL-TRIM21 interaction to protect NCL from degradation. Co-IP, ubiquitination assay with site mutagenesis (K239), circ0006646 silencing, multi-omics, in vivo xenograft Advanced science Medium 38357830
2023 TRIM21 restricts influenza A virus subtypes H3/H5/H9 (but not H1/H7) by binding to residue R95 of M1 matrix protein and facilitating K48-linked ubiquitination of M1 K242 for proteasomal degradation. Recombinant viruses with M1 R95K or K242R mutations were resistant to TRIM21. Co-IP, ubiquitination assay, site-directed mutagenesis (R95K, K242R), proteasomal degradation assays, recombinant virus rescue PLoS pathogens High 37343022
2024 TRIM21 promotes K63-linked ubiquitination of PD-1 at K233, stabilizing PD-1 by antagonizing its K48-linked ubiquitination and degradation. Trim21 KO significantly decreases PD-1 expression, enhances CD8+ T cell activation, and sensitizes tumors to anti-CTLA-4 immunotherapy. Co-IP, ubiquitination assay with linkage and site (K233) mutagenesis, Trim21 KO mice, CD8+ T cell activation assays, in vivo tumor models Molecular therapy High 39905727
2024 TRIM21 promotes K63-linked ubiquitination of TAT (tyrosine aminotransferase) at K136 via interaction involving H336/H338 of TRIM21; this ubiquitination impairs TAT dimerization and mitochondrial localization, inhibiting cardiolipin-dependent mitophagy and GBC liver metastasis. Co-IP with TRIM21 domain mutagenesis (H336/H338), ubiquitination assay (K63, K136), TAT dimerization assay, mitochondrial localization assay, in vivo metastasis model Cancer letters Medium 38697462
2024 TRIM21 mediates K63-linked ubiquitination and lysosomal degradation of AXL receptor; STAMBPL1 (a deubiquitinase) antagonizes this to stabilize AXL, promoting EMT and immune evasion in kidney renal clear cell carcinoma. Co-IP, ubiquitination assay (K63 linkage), lysosomal inhibitor experiments, STAMBPL1 KD with rescue experiments Advanced science Medium 39527690
2023 EGFR activation induces c-Src-mediated phosphorylation of CD47 at Y288, which inhibits TRIM21-mediated K99/K102 polyubiquitylation and degradation of CD47, leading to CD47 accumulation and tumor immune evasion. Co-IP, ubiquitination assay with site mutagenesis (Y288F, K99/102R knock-in), macrophage phagocytosis assay, in vivo brain tumor model Advanced science High 37541303
2025 Small-molecule ligands to TRIM21 identified by DEL technology; crystallography confirmed ligand interaction with TRIM21. Treatment induced TRIM21-dependent, ubiquitin-proteasome-dependent degradation of NUP155 (primary target) and GLE1 (passenger), impairing nuclear envelope integrity. DNA-Encoded Library screen, crystallography, proteomic profiling, TRIM21 KO validation, proteasome inhibitor, immunofluorescence ACS chemical biology High 40247740
2024 USP28 deubiquitinates and stabilizes TRIM21 in cardiomyocytes; stabilized TRIM21 negatively regulates Nrf2 antioxidant response, increasing oxidative stress and promoting cardiac hypertrophy. USP28 CKO protects against Ang II- and TAC-induced cardiac dysfunction. Co-IP/mass spectrometry (substrate screen), cardiomyocyte-specific USP28 KO mice, deubiquitination assay, Nrf2 pathway readout, cardiac hypertrophy models Theranostics Medium 39431010
2022 CDK2 phosphorylates PXR at Ser350, promoting PXR dissociation from Hsp90/DNAJC7 and subsequent TRIM21-mediated PXR ubiquitination and proteasomal degradation. Co-IP, ubiquitination assay, CDK2 kinase assay, PXR-S350 phosphorylation site mutagenesis, Hsp90/DNAJC7 interaction assay Cells Medium 35053380
2024 TRIM21 interacts with ERK1/2 through its PRY-SPRY domain and catalyzes K27-linked ubiquitination of ERK1/2; this ubiquitination promotes ERK1/2-MEK1/2 interaction and subsequent ERK1/2 phosphorylation. Excess TRIM21 suppresses ERK1/2 phosphorylation by activating negative feedback pathways. CRISPR-Cas9 screen, Co-IP with domain mapping (PRY-SPRY), ubiquitination assay (K27 linkage), NanoBiT protein interaction assay, RNA-seq Neuro-oncology Medium 39533840
2024 TRIM21 interacts with ACSL4 and promotes its ubiquitination and degradation; USP15 (deubiquitinase) counteracts this by deubiquitinating and stabilizing ACSL4. The balance between TRIM21 and USP15 determines ACSL4 levels and imatinib sensitivity in gastrointestinal stromal tumors. Co-IP, ubiquitination assay, deubiquitination assay, shRNA knockdown, xenograft mouse model British journal of cancer Medium 38182686
2024 TRIM21 interacts with and promotes K48-linked ubiquitination of CNOT4 at K239 (via K48 and K6 linkage) when complexed with TNKS1BP1, leading to CNOT4 degradation and downstream autophagy/lipid reprogramming effects in HCC. Co-IP, ubiquitination assay with site mutagenesis (K239), mass spectrometry, in vivo HCC models Cell death & disease Medium 39019859
2024 TRIM21 catalyzes K48-linked ubiquitination of TRPV2 at K295 in myeloid cells, promoting TRPV2 lysosomal/proteasomal degradation and reducing viral spread. TRPV2-K295R mutant is resistant to TRIM21-dependent degradation and promotes viral infection more profoundly than wild-type TRPV2. Co-IP, ubiquitination assay with site mutagenesis (K295R), Trim21-/- mice, TRPV2 KO reconstitution, viral infection assays (HSV-1, VSV) Cell reports High 38613787
2024 TRIM21 promotes K48-linked ubiquitination of SREBF1, leading to its proteasomal degradation and consequent downregulation of lipogenic enzyme expression (reducing lipid accumulation) in renal cell carcinoma. Co-IP, immunoprecipitation, ubiquitination assay, TRIM21 KO/OE, metabolomics, Oil Red O staining, in vivo orthotopic model Journal of experimental & clinical cancer research Medium 36694250
2024 ANTIBODIES targeting CCHFV nucleoprotein (NP) protect against lethal CCHFV challenge through TRIM21-dependent mechanisms (intracellular Fc receptor function); TRIM21-deficient vaccinated mice cannot control infection despite robust CCHFV-specific immunity. Passive transfer of NP-immune sera confers TRIM21-dependent protection. TRIM21 KO mice, passive serum transfer, Fc-gamma receptor and complement KO controls, lethal challenge model Nature communications High 39455551
2023 TRIM21 promotes ubiquitination of Sohlh2 and its proteasomal degradation, suppressing M2 macrophage polarization and triple-negative breast cancer progression. Co-IP, ubiquitination assay, TRIM21 KO/OE in macrophages, M2 polarization assays, in vivo metastasis model Cell death & disease Medium 38123542
2024 TRIM21 promotes K63-linked ubiquitination and promotes nuclear translocation of PKM2 in astrocytes; nuclear PKM2 phosphorylates STAT3 and NF-κB and interacts with c-Myc, promoting astrocyte activation and glycolysis in experimental autoimmune encephalomyelitis. Co-IP, ubiquitination assay, TRIM21 OE/KD in primary astrocytes, nuclear PKM2 activity assays, intracerebroventricular lentiviral KD, EAE mouse model eLife Medium 39264698
2023 TRIM21 mutually regulates TRIM8 via K48-linked ubiquitination: TRIM21 promotes proteasomal degradation of TRIM8, and TRIM8 reciprocally promotes degradation of TRIM21 via K48-linked ubiquitination. Co-IP, ubiquitination assay (K48 linkage), proteasome inhibitor experiments, expression correlation in NSCLC and RCC clinical samples Oncogene Medium 37914816

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Molecular cell 191 26942676
2010 Host cell invasion and virulence mediated by Candida albicans Ssa1. PLoS pathogens 161 21085601
2017 Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proceedings of the National Academy of Sciences of the United States of America 157 28049840
2012 The immunobiology of Ro52 (TRIM21) in autoimmunity: a critical review. Journal of autoimmunity 147 22402340
2003 Candida albicans Ssa1/2p is the cell envelope binding protein for human salivary histatin 5. The Journal of biological chemistry 132 12761219
2019 TRIM21-From Intracellular Immunity to Therapy. Frontiers in immunology 121 31555278
2020 TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism. Nature communications 116 32312982
2023 TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models. Nature communications 113 36797289
2023 Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules. Autophagy 95 36692217
2023 UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders. Cell metabolism 95 37343564
2021 TRIM21 - A potential novel therapeutic target in cancer. Pharmacological research 94 33508433
2015 TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. Immunological reviews 87 26497531
2021 TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease. Frontiers in immunology 84 34552597
2017 TRIM21 and the Function of Antibodies inside Cells. Trends in immunology 80 28807517
2024 Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders. Cell 77 39488207
2023 TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury. Life sciences 76 36958437
2021 TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization. Cell death and differentiation 73 34511601
2023 The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer. The Journal of clinical investigation 62 36749630
2023 Cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy in mouse models. Science (New York, N.Y.) 61 36996217
2018 Decreased expression of TRIM21 indicates unfavorable outcome and promotes cell growth in breast cancer. Cancer management and research 61 30288100
2022 Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21-mediated ubiquitination/degradation of STAT1 in a GTP binding-dependent modality. Cancer communications (London, England) 59 36353796
2020 Viral nucleoprotein antibodies activate TRIM21 and induce T cell immunity. The EMBO journal 59 33258165
2023 EGFR-Induced and c-Src-Mediated CD47 Phosphorylation Inhibits TRIM21-Dependent Polyubiquitylation and Degradation of CD47 to Promote Tumor Immune Evasion. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 56 37541303
2019 TRIM21-mediated proteasomal degradation of SAMHD1 regulates its antiviral activity. EMBO reports 56 31797533
2022 ARPC1B promotes mesenchymal phenotype maintenance and radiotherapy resistance by blocking TRIM21-mediated degradation of IFI16 and HuR in glioma stem cells. Journal of experimental & clinical cancer research : CR 55 36380368
2009 High Ro52 expression in spontaneous and UV-induced cutaneous inflammation. The Journal of investigative dermatology 54 19194477
2023 TRIM21 deficiency protects against atrial inflammation and remodeling post myocardial infarction by attenuating oxidative stress. Redox biology 53 36996623
2018 TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination. Proceedings of the National Academy of Sciences of the United States of America 53 30209217
2020 The E3 Ubiquitin Ligase TRIM21 Promotes HBV DNA Polymerase Degradation. Viruses 50 32245233
2023 TRIM21-Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 49 37587773
2023 UBE2S interacting with TRIM21 mediates the K11-linked ubiquitination of LPP to promote the lymphatic metastasis of bladder cancer. Cell death & disease 48 37422473
2023 Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth. The Journal of clinical investigation 47 37066876
2009 rs660 polymorphism in Ro52 (SSA1; TRIM21) is a marker for age-dependent tolerance induction and efficiency of alloimmunization in sickle cell disease. Molecular immunology 47 19201475
2022 TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination. Nucleic acids research 46 35048968
2012 Autoantigen TRIM21/Ro52 as a Possible Target for Treatment of Systemic Lupus Erythematosus. International journal of rheumatology 46 22701487
2023 Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling. Bone research 43 37884520
2023 TRIM21 attenuates renal carcinoma lipogenesis and malignancy by regulating SREBF1 protein stability. Journal of experimental & clinical cancer research : CR 42 36694250
2023 BCKDK regulates breast cancer cell adhesion and tumor metastasis by inhibiting TRIM21 ubiquitinate talin1. Cell death & disease 42 37460470
2023 TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer. Cell death & disease 41 38123542
2009 Ssa1 overexpression and [PIN(+)] variants cure [PSI(+)] by dilution of aggregates. Journal of molecular biology 41 19422835
2014 Global transcript and phenotypic analysis of yeast cells expressing Ssa1, Ssa2, Ssa3 or Ssa4 as sole source of cytosolic Hsp70-Ssa chaperone activity. BMC genomics 39 24628813
2020 TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis. Frontiers in immunology 38 32117252
2023 Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination. Journal for immunotherapy of cancer 36 38040417
2024 TRIM21 induces selective autophagic degradation of c-Myc and sensitizes regorafenib therapy in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America 35 39388269
2023 A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation. Nature communications 35 37925433
2023 TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2. Cell chemical biology 34 37354905
2023 Multiple Roles of TRIM21 in Virus Infection. International journal of molecular sciences 33 36675197
2016 Coordinated Neutralization and Immune Activation by the Cytosolic Antibody Receptor TRIM21. Journal of virology 33 26937031
2014 TRIM21-dependent intracellular antibody neutralization of virus infection. Progress in molecular biology and translational science 33 25595804
2013 Common and specific associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies in systemic lupus erythematosus. TheScientificWorldJournal 32 24294139
2020 CSN6-TRIM21 axis instigates cancer stemness during tumorigenesis. British journal of cancer 31 32225170
2023 TRIM21 restricts influenza A virus replication by ubiquitination-dependent degradation of M1. PLoS pathogens 30 37343022
2024 Integrated Multiomics Reveals Silencing of has_circ_0006646 Promotes TRIM21-Mediated NCL Ubiquitination to Inhibit Hepatocellular Carcinoma Metastasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 38357830
2009 Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice. The Journal of experimental medicine 27 19635865
2023 USP25 promotes hepatocellular carcinoma progression by interacting with TRIM21 via the Wnt/β-catenin signaling pathway. Chinese medical journal 26 37439386
2022 Functional skewing of TRIM21-SIRT5 interplay dictates IL-1β production in DSS-induced colitis. EMBO reports 26 35770730
2024 Association of Combined Anti-Ro52/TRIM21 and Anti-Ro60/SSA Antibodies With Increased Sjögren Disease Severity Through Interferon Pathway Activation. Arthritis & rheumatology (Hoboken, N.J.) 24 38130019
2024 Trim21-mediated CCT2 ubiquitination suppresses malignant progression and promotes CD4+T cell activation in breast cancer. Cell death & disease 24 39079960
2021 The molecular mechanisms that drive intracellular neutralization by the antibody-receptor and RING E3 ligase TRIM21. Seminars in cell & developmental biology 23 34823983
2018 The Sjögren's syndrome-associated autoantigen Ro52/TRIM21 modulates follicular B cell homeostasis and immunoglobulin production. Clinical and experimental immunology 23 30178506
2024 TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1-Mediated Arachidonic Acid Metabolism. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 39739616
2023 TRIM21-dependent target protein ubiquitination mediates cell-free Trim-Away. Cell reports 22 36807144
2023 TRIM21 promotes ubiquitination of SARS-CoV-2 nucleocapsid protein to regulate innate immunity. Journal of medical virology 22 37185839
2023 EDARADD promotes colon cancer progression by suppressing E3 ligase Trim21-mediated ubiquitination and degradation of Snail. Cancer letters 21 37838280
2023 The interconnected roles of TRIM21/Ro52 in systemic lupus erythematosus, primary Sjögren's syndrome, cancers, and cancer metabolism. Cancer cell international 21 37993883
2025 Chemically Induced Nuclear Pore Complex Protein Degradation via TRIM21. ACS chemical biology 20 40247740
2024 SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation. Cancer letters 20 38360141
2023 TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting prosurvival autophagy. Blood advances 19 37083684
2022 TRIM21 deficiency promotes cell proliferation and tumorigenesis via regulating p21 expression in ovarian cancer. Bioengineered 19 35226825
2022 TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination of ISG12a. Journal of immunology (Baltimore, Md. : 1950) 19 36426955
2024 Cardiomyocyte-derived USP28 negatively regulates antioxidant response and promotes cardiac hypertrophy via deubiquitinating TRIM21. Theranostics 18 39431010
2024 STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 39527690
2017 Ro52/TRIM21-deficient expression and function in different subsets of peripheral blood mononuclear cells is associated with a proinflammatory cytokine response in patients with idiopathic inflammatory myopathies. Clinical and experimental immunology 18 27936488
2025 TRIM21-mediated METTL3 degradation promotes PDAC ferroptosis and enhances the efficacy of Anti-PD-1 immunotherapy. Cell death & disease 17 40175350
2024 MDM4 inhibits ferroptosis in p53 mutant colon cancer via regulating TRIM21/GPX4 expression. Cell death & disease 17 39543140
2023 Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators. JCI insight 17 37937648
2022 Phosphorylation-Induced Ubiquitination and Degradation of PXR through CDK2-TRIM21 Axis. Cells 17 35053380
2024 Antibodies targeting the Crimean-Congo Hemorrhagic Fever Virus nucleoprotein protect via TRIM21. Nature communications 16 39455551
2024 TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors. British journal of cancer 15 38182686
2024 TRIM21-mediated ubiquitination of SQSTM1/p62 abolishes its Ser403 phosphorylation and enhances palmitic acid cytotoxicity. Autophagy 15 39172027
2025 TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas. Neuro-oncology 14 39533840
2023 Mutual regulation between TRIM21 and TRIM8 via K48-linked ubiquitination. Oncogene 14 37914816
2022 MICALL2 as a substrate of ubiquitinase TRIM21 regulates tumorigenesis of colorectal cancer. Cell communication and signaling : CCS 14 36307841
2020 Co-expressing GroEL-GroES, Ssa1-Sis1 and Bip-PDI chaperones for enhanced intracellular production and partial-wall breaking improved stability of porcine growth hormone. Microbial cell factories 14 32070347
2023 TRIM21 Promotes Rabies Virus Production by Degrading IRF7 through Ubiquitination. International journal of molecular sciences 13 37446070
2023 Ro52/TRIM21 - From host defense to autoimmunity. Cellular immunology 13 37857191
2016 Surveillance for Intracellular Antibody by Cytosolic Fc Receptor TRIM21. Antibodies (Basel, Switzerland) 13 31558002
2025 Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy. Molecular therapy : the journal of the American Society of Gene Therapy 12 39905727
2025 TRIM21-NUP98 Interface Accommodates Structurally Diverse Molecular Glue Degraders. ACS chemical biology 12 40204658
2024 Viral infection and spread are inhibited by the polyubiquitination and downregulation of TRPV2 channel by the interferon-stimulated gene TRIM21. Cell reports 12 38613787
2024 TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer. Cancer letters 12 38697462
2024 TNKS1BP1 facilitates ubiquitination of CNOT4 by TRIM21 to promote hepatocellular carcinoma progression and immune evasion. Cell death & disease 12 39019859
2024 Upregulated expression of ubiquitin ligase TRIM21 promotes PKM2 nuclear translocation and astrocyte activation in experimental autoimmune encephalomyelitis. eLife 12 39264698
2022 Fish TRIM21 exhibits antiviral activity against grouper iridovirus and nodavirus infection. Fish & shellfish immunology 12 35764286
2022 Anti-Ro52/TRIM21 serological subsets identify differential clinical and laboratory parameters. Clinical rheumatology 12 35871174
2019 TRIM21 controls Toll-like receptor 2 responses in bone-marrow-derived macrophages. Immunology 12 31755557
2010 Heat, pH induced aggregation and surface hydrophobicity of S. cerevesiae Ssa1 protein. The protein journal 12 20835845
2022 UBE2L3 Reduces TRIM21 Expression and IL-1β Secretion in Epidermal Keratinocytes and Improves Psoriasis-Like Skin. The Journal of investigative dermatology 11 36502938
2022 Alternative exon usage in TRIM21 determines the antigenicity of Ro52/TRIM21 in systemic lupus erythematosus. JCI insight 10 36040804
2021 TRIM21 Polymorphisms are associated with Susceptibility and Clinical Status of Oral Squamous Cell Carcinoma patients. International journal of medical sciences 10 34220328

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