Affinage

TRIM21

E3 ubiquitin-protein ligase TRIM21 · UniProt P19474

Length
475 aa
Mass
54.2 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 46 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM21 is a cytosolic E3 ubiquitin ligase that functions as the cell's primary intracellular antibody receptor and a broad-spectrum regulator of protein turnover, innate immunity, redox homeostasis, and metabolic signaling. Its PRYSPRY/B30.2 domain binds antibody Fc regions with high affinity and also engages diverse cellular substrates, while its RING domain catalyzes K48-, K63-, K27-, and K33-linked ubiquitination; upon detecting antibody-coated pathogens or protein aggregates (including viruses, bacteria, and tau seeds) in the cytosol, TRIM21 ubiquitinates target proteins to drive proteasomal and autophagic degradation and simultaneously activates innate immune signaling through K27-linked ubiquitination of MAVS (PMID:18420815, PMID:28049840, PMID:29743353, PMID:36807144, PMID:36996217). Beyond intracellular immunity, TRIM21 ubiquitinates a wide array of substrates—including p62/SQSTM1 (K63-K7), GPX4, GSDMD, mutant p53, VDAC2, METTL3, PD-1 (K63-K233), MST2, VHL, and lipogenic enzymes—to regulate the Nrf2 antioxidant response, ferroptosis, pyroptosis, Hippo-YAP signaling, and hepatic lipid metabolism (PMID:26942676, PMID:34511601, PMID:36749630, PMID:36797289, PMID:37343564, PMID:37354905). TRIM21 activity is itself regulated by HDAC6-mediated deacetylation at K385/K387 (required for dimerization), UBE2M-mediated neddylation at K129/K134 (enhancing E3 activity), ERK2 phosphorylation at T396 (disrupting substrate interaction), oxidative inactivation at RING-domain cysteines, and USP28-mediated deubiquitination (PMID:32796032, PMID:37343564, PMID:39388269, PMID:39172027, PMID:39431010).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Early structural work established that the RBCC region of TRIM21 requires Zn²⁺ for folding and that the coiled-coil harbors autoepitopes linked to congenital heart block, providing the first domain-level architecture of the protein.

    Evidence Fluorescence/CD spectroscopy, MALDI-TOF proteolysis, Zn²⁺ binding analysis

    PMID:15964842

    Open questions at the time
    • No enzymatic activity demonstrated
    • Autoepitope mapping lacked patient-derived functional validation
  2. 2008 High

    Two foundational discoveries defined TRIM21's dual identity: structural and biophysical studies revealed its PRYSPRY domain as a high-affinity IgG Fc receptor, while chimeric domain experiments confirmed its RING domain possesses E3 ubiquitin ligase activity, establishing the mechanistic basis for antibody-dependent intracellular neutralization.

    Evidence X-ray crystallography, pre-steady-state kinetics, mutagenesis of Fc-binding interface; in vitro E3 ligase reconstitution with baculovirus-purified protein and EM of capsid binding

    PMID:18420815 PMID:18799572

    Open questions at the time
    • No in vivo demonstration of intracellular antibody sensing
    • Ubiquitination substrates in cells unknown
  3. 2016 High

    The first endogenous cellular substrate was defined: TRIM21 K63-ubiquitinates p62/SQSTM1 at K7, disrupting p62 oligomerization and Keap1 sequestration, thereby suppressing the Nrf2 antioxidant response—establishing TRIM21 as a regulator of redox homeostasis beyond immunity.

    Evidence In vitro ubiquitination with K7 mutagenesis, TRIM21 KO mice, cellular imaging

    PMID:26942676

    Open questions at the time
    • Whether oxidative stress directly modulates TRIM21 activity was unknown
    • Breadth of non-immune substrates uncharacterized
  4. 2017 High

    TRIM21 was shown to neutralize antibody-coated tau seeds in the cytosol via proteasomal and p97/VCP-dependent degradation, extending the ADIN concept from viruses to misfolded protein aggregates relevant to neurodegeneration.

    Evidence Fluorescence-based tau seeding assay, TRIM21 KO, proteasome/p97 inhibitors, live-cell imaging

    PMID:28049840

    Open questions at the time
    • In vivo neuronal relevance not yet demonstrated at this point
    • Whether TRIM21 ubiquitinates tau directly or the antibody was unclear
  5. 2018 High

    TRIM21 was established as a positive regulator of innate immune signaling through K27-linked ubiquitination of MAVS at K325, promoting TBK1 recruitment during RNA virus infection; simultaneously, in vivo KO studies proved TRIM21's physiological role in antibody-dependent neutralization of adenovirus and regulation of adaptive immunity.

    Evidence Co-IP with domain deletions, K325 mutagenesis, TBK1 recruitment; TRIM21 KO mice with adenoviral challenge and transcriptomics

    PMID:29743353 PMID:30209217

    Open questions at the time
    • Whether TRIM21 signals through pathways beyond MAVS/TBK1 was unexplored
    • Relative contribution of proteasomal vs. autophagic degradation in vivo unclear
  6. 2020 High

    Post-translational regulation of TRIM21 was defined: HDAC6 deacetylates K385/K387 to promote homodimerization and E3 activity, while antibody-dependent antigen processing was shown to generate CTL epitopes, linking humoral and cellular immunity through TRIM21.

    Evidence HDAC6 KD/inhibition, acetylation site mutagenesis (K385/387R), viral accumulation assay; TRIM21 KO mice with LCMV, CTL and antigen presentation assays

    PMID:32796032 PMID:33258165

    Open questions at the time
    • Whether acetylation-deacetylation cycle is dynamically regulated during infection unknown
    • Other writers/erasers of TRIM21 PTMs not yet identified
  7. 2021 High

    TRIM21's role in inflammasome biology was established through its interaction with GSDMD: it maintains GSDMD stability at rest and promotes GSDMD-N oligomerization during pyroptosis, with KO mice protected from LPS-induced inflammation and colitis.

    Evidence Co-IP with domain deletions, TRIM21 KO mice, NLRP3/NLRC4 inflammasome assays, DSS colitis model

    PMID:34511601

    Open questions at the time
    • Ubiquitination sites on GSDMD not mapped
    • Whether TRIM21 directly ubiquitinates GSDMD or acts as a scaffold unclear
  8. 2022 High

    IgG subclass-specific differences in TRIM21 engagement were explained: IgG3's extended flexible hinge enables superior TRIM21 recruitment independent of Fc affinity, and a TRIM21-SIRT5 positive feedback loop through K48-linked degradation of SIRT5 and sustained TRIM21 acetylation was identified as an amplifier of inflammatory signaling.

    Evidence IgG subclass hinge mutants with TRIM21 recruitment and neutralization assays; SIRT5 ubiquitination/degradation assay, K351 acetylation, DSS colitis model

    PMID:35486676 PMID:35770730

    Open questions at the time
    • Whether hinge-dependent recruitment involves conformational changes in TRIM21 unknown
    • SIRT5-TRIM21 feedback loop not validated in non-macrophage contexts
  9. 2023 High

    A burst of substrate discovery revealed TRIM21 as a pleiotropic E3 ligase: it ubiquitinates mutant p53 (but not WT) for degradation to suppress gain-of-function tumorigenesis, GPX4 to sensitize cells to ferroptosis, VDAC2 to suppress cGAS-STING signaling, MST2 (K63-K473) to activate Hippo pathway, PD-1 (K63-K233) to stabilize the checkpoint receptor, c-Myc (K63-K148) for autophagic degradation, and multiple metabolic enzymes (PEPCK1, FASN, ChREBP, METTL3) to regulate lipid/glucose metabolism. Additionally, neddylation by UBE2M at K129/K134 and phosphorylation by ERK2 at T396 were identified as key regulatory PTMs.

    Evidence Systematic Co-IP, site-specific mutagenesis, ubiquitination assays across multiple substrate classes; KO/KI mouse models for p53R172H, I/R kidney injury, NASH, CRC; neddylation/phosphorylation assays with site mutagenesis

    PMID:36749630 PMID:36797289 PMID:36958437 PMID:37249651 PMID:37343564 PMID:37354905 PMID:37937648 PMID:39388269 PMID:39905727 PMID:40175350

    Open questions at the time
    • Many substrates identified by single labs without independent replication
    • How substrate selectivity is achieved among dozens of targets is mechanistically undefined
    • Relative importance of individual substrates in physiological contexts unclear
  10. 2023 High

    The mechanism of Trim-Away/ADIN was refined: TRIM21 ubiquitinates the target protein (not itself), and oxidative inactivation of TRIM21 at RING-domain cysteines C92/C111/C114 was identified as an intrinsic shutoff mechanism; in vivo, TRIM21 was shown to be essential for antibody-mediated protection against tau pathology in neurons.

    Evidence Cell-free Xenopus extract with chemical methylation of TRIM21 lysines and target lysine deletion; cysteine mutagenesis in KO MEFs; TRIM21 KO mice with passive anti-tau antibody transfer

    PMID:36807144 PMID:36996217 PMID:39172027

    Open questions at the time
    • Structure of full-length TRIM21 engaged with antibody-target complex not determined
    • Oxidative inactivation threshold and reversibility in vivo unknown
  11. 2024 High

    TRIM21 emerged as a pharmacologically tractable E3 ligase: molecular glue (S)-ACE-OH induces TRIM21-NUP98 interaction enabling selective degradation of multimeric nuclear pore proteins, requiring substrate-induced TRIM21 clustering for activation; USP28 was identified as a deubiquitinase stabilizing TRIM21; and small-molecule ligands from DEL screening induce NUP155 degradation with crystal structures of the TRIM21-ligand interface.

    Evidence Molecular glue screen with proteomics and clustering requirement; USP28 Co-IP/MS with cardiomyocyte-specific KO mice; DEL screening with crystallography and TRIM21 KO rescue

    PMID:39431010 PMID:39488207 PMID:40247740

    Open questions at the time
    • Whether clustering-dependent activation applies to all TRIM21 substrates is untested
    • Selectivity window of molecular glue/DEL ligands across the proteome requires broader profiling
    • Therapeutic index of TRIM21-targeted degraders not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how TRIM21 achieves selectivity among its dozens of substrates in different cellular contexts; (2) the full structural basis for antibody-TRIM21-target ternary complex formation and activation by clustering; (3) whether TRIM21's roles in ferroptosis, pyroptosis, and metabolism are physiologically dominant or context-dependent; and (4) whether TRIM21-based targeted protein degradation can be developed into therapeutic platforms.
  • No full-length TRIM21 structure in complex with antibody and target
  • Substrate prioritization hierarchy unknown
  • In vivo relevance of many single-lab substrate discoveries not independently confirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 24 GO:0098772 molecular function regulator activity 5 GO:0016874 ligase activity 3
Localization
GO:0005829 cytosol 6 GO:0005634 nucleus 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-392499 Metabolism of proteins 5 R-HSA-5357801 Programmed Cell Death 5 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1430728 Metabolism 2
Partners
GSDMDHDAC6MAVSSIRT5SQSTM1TRIM8UBE2MUSP28

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TRIM21 is a cytosolic IgG receptor that binds the Fc fragment using its PRYSPRY domain, simultaneously targeting conserved hot-spot residues on both Ig domains of the Fc fragment via a preformed multisite interface. The binding mechanism is structurally, thermodynamically, and kinetically conserved across species. Structural analysis, pre-steady-state kinetics, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 18420815
2008 A chimeric TRIM5alpha protein containing the RING domain from TRIM21 displays E3 ligase activity in vitro, self-ubiquitylates in the presence of ubiquitin-activating and conjugating enzymes, and specifically associates with HIV-1 capsid-like complexes via the B30.2(SPRY) domain. In vitro E3 ligase assay, baculovirus purification, negative stain EM, capsid binding assay Journal of virology High 18799572
2016 TRIM21 directly interacts with SQSTM1/p62 and ubiquitylates p62 at lysine 7 via K63-linkage, abrogating p62 oligomerization and sequestration of client proteins (including Keap1), thereby suppressing the antioxidant response. TRIM21-deficient cells show enhanced antioxidant response and reduced cell death under oxidative stress. Co-IP, in vitro ubiquitination assay, K7 mutagenesis, TRIM21 KO mice, cellular imaging Molecular cell High 26942676
2017 TRIM21 binds antibody-coated tau seeds entering the cytosol and neutralizes them through proteasomal and p97/VCP AAA-ATPase activity, inhibiting seeded tau aggregation in a manner analogous to intracellular antiviral immunity. Fluorescence-based seeding assay, TRIM21 knockdown/KO, proteasome and p97 inhibitors, live-cell imaging Proceedings of the National Academy of Sciences of the United States of America High 28049840
2018 TRIM21 interacts with MAVS via its PRY-SPRY domain and catalyzes K27-linked polyubiquitination of MAVS at Lys325 via its RING domain, promoting TBK1 recruitment to MAVS and enhancing innate immune signaling during RNA viral infection. Co-IP, knockdown, domain deletion mutants, lysine substitution mutagenesis of MAVS, TBK1 recruitment assay Journal of virology High 29743353
2018 TRIM21 mediates antibody-dependent intracellular neutralization (ADIN) of adenovirus in vivo; genetic KO of TRIM21 or a single antibody point mutation restores transgene expression to near-naïve levels. TRIM21 also blocks CTL induction by adenoviral vaccine vectors and drives upregulation of hundreds of innate/intrinsic immune genes. TRIM21 KO mice, antibody point mutant, transcriptomics, in vivo viral challenge Proceedings of the National Academy of Sciences of the United States of America High 30209217
2020 HDAC6 deacetylates TRIM21 at lysine 385 and lysine 387 via interaction through the PRYSPRY motif, promoting TRIM21 homodimerization. Hyperacetylation of TRIM21 (by HDAC6 inhibition) blocks dimerization and ubiquitination activity, impairing antibody-dependent intracellular neutralization of viruses. Co-IP, HDAC6 KD/inhibition, acetylation site mutagenesis (K385/387R), viral accumulation assay The Journal of biological chemistry High 32796032
2020 TRIM21 uses anti-nucleoprotein antibodies to target nucleoprotein for cytosolic degradation, generating CTL epitopes that drive cytotoxic T cell responses against LCMV, demonstrating synergy between antibody-mediated and T cell-mediated immunity. TRIM21 KO mice, LCMV infection model, CTL assay, antigen presentation assay The EMBO journal High 33258165
2020 HPV E7 recruits the E3 ligase TRIM21 to ubiquitinate and degrade the IFI16 inflammasome, inhibiting pyroptosis and enabling immune escape. Interaction between HPV E7, IFI16, and TRIM21 was confirmed by mass spectrometry and immunoprecipitation. Mass spectrometry, co-IP, ubiquitination assay, pyroptosis assay International journal of biological sciences Medium 33061806
2020 TRIM21 promotes ubiquitination and proteasomal degradation of HBV DNA polymerase (Pol) via interaction with the TP domain of Pol through its SPRY domain and RING domain E3 activity, with Lys260 and Lys283 of HBV Pol as ubiquitination targets, restricting HBV DNA replication. FLAG affinity purification, mass spectrometry, Co-IP, ubiquitination assay, domain deletion mutants Viruses Medium 32245233
2021 TRIM21 interacts with GSDMD via its PRY-SPRY domain, maintaining GSDMD stability in resting cells and promoting GSDMD-N oligomerization/aggregation during pyroptosis. TRIM21 KO mice are protected from LPS-induced inflammation and DSS-induced colitis. Co-IP, domain deletion mutants, TRIM21 KO mice, pyroptosis/NLRP3/NLRC4 inflammasome assays Cell death and differentiation High 34511601
2021 TRIM21 promotes K48-linked ubiquitination and proteasomal degradation of HBx protein, leading to impaired HBx-mediated degradation of Smc6 and suppression of HBV replication. Both RING and PRY-SPRY domains are required. Co-IP, ubiquitination assay, Smc6 stabilization assay, hydrodynamic injection HBV mouse model, domain mutants Antiviral research Medium 34097931
2022 IgG3 mediates superior TRIM21-dependent intracellular antiviral immunity compared to other IgG subclasses due to its uniquely extended and flexible hinge region, which facilitates improved TRIM21 recruitment independently of Fc binding affinity. TRIM21 also synergizes with complement C1/C4-mediated lysosomal degradation in a hinge-dependent manner. IgG subclass comparison, hinge mutants, TRIM21 recruitment assay, viral neutralization, complement assays Science immunology High 35486676
2022 LPS-induced macrophage polarization enhances TRIM21-SIRT5 interaction, promoting K48-linked ubiquitination and degradation of SIRT5 by TRIM21. SIRT5 degradation sustains acetylation of TRIM21 at Lys351, increasing its E3 ligase activity in a positive feedback loop that enhances IL-1β production. Co-IP, ubiquitination assay, acetylation assay, macrophage polarization, DSS colitis model EMBO reports Medium 35770730
2023 TRIM21 directly interacts with and ubiquitinates SQSTM1/p62 at K7 via K63-linkage; this ubiquitination abolishes p62 PB1 domain dimerization and S403 phosphorylation by TBK1, suppressing p62 aggregation and antioxidant sequestration. TRIM21 itself is inactivated by oxidation at C92, C111, and C114 via disulfide bond formation. In vitro ubiquitination, mutagenesis (K7, S403, cysteine residues), TBK1 phosphorylation assay, TRIM21 KO MEFs Autophagy High 39172027
2023 UBE2M neddylates TRIM21 at K129/K134, leading to increased E3 ubiquitin ligase activity of TRIM21 toward VHL, promoting VHL ubiquitination-mediated degradation, which stabilizes HIF-1α and increases IL-1β production in macrophages. Co-IP, neddylation assay, UBE2M KO macrophages, VHL/HIF-1α ubiquitination assay, site mutagenesis Cell metabolism High 37343564
2023 TRIM21 catalyzes K63-linked ubiquitination of the stress granule core protein G3BP1, inhibiting its liquid-liquid phase separation in vitro and suppressing stress granule formation; autophagy receptors p62 and NDP52 mediate stress granule elimination. E3 ligase screen in SGs, Co-IP, in vitro LLPS assay, TRIM21 KD/OE, autophagy receptor KO Autophagy Medium 36692217
2023 TRIM21 directly interacts with mutant p53 (but not wild-type p53), promoting its ubiquitination and proteasomal degradation to suppress mutant p53 gain-of-function. TRIM21 deletion in p53R172H knockin mice caused mutp53 accumulation in normal tissues, earlier tumor onset, and shortened lifespan. Co-IP, ubiquitination assay, TRIM21/p53R172H double KI mice, cell-based KO experiments The Journal of clinical investigation High 36749630
2023 TRIM21 ubiquitylates GPX4 (glutathione peroxidase 4), promoting its degradation and sensitizing cells to ferroptosis. GPX4 was confirmed as a direct substrate of TRIM21; TRIM21 KO protects against I/R-induced ferroptosis and acute kidney injury in mice. Co-IP, ubiquitination assay, TRIM21 KO mice I/R model, overexpression in HK-2 cells Life sciences Medium 36958437
2023 TRIM21 promotes K48-linked ubiquitination and degradation of VDAC2, inhibiting VDAC2 oligomer pore formation required for mitochondrial DNA release, thereby suppressing cGAS/STING pathway activation and antitumour immunity after irradiation. TRIM21 KO in NPC cells, ubiquitination assay, VDAC2 co-IP, mtDNA release assay, cGAS/STING signaling readout Nature communications High 36797289
2023 TRIM21 ubiquitinates SARS-CoV-2 nucleocapsid (N) protein at Lys375 via polyubiquitination, targeting N for proteasomal degradation, which inhibits viral particle assembly. This activity extends to N proteins from SARS-CoV-2 variants, SARS-CoV, and MERS-CoV. Co-IP/mass spectrometry, ubiquitination assay with site mutagenesis, proteasomal degradation assay Journal of medical virology Medium 37185839
2023 TRIM21 directly interacts with and ubiquitinates MST2 at K473 via K63-linkage, enabling MST2 homodimerization and enhanced kinase activity, which inactivates YAP and inhibits EMT/metastasis in colorectal cancer. Co-IP, K473 mutagenesis, ubiquitination assay, MST2 kinase assay, YAP phosphorylation readout, CRC organoids Cell chemical biology Medium 37354905
2023 TRIM21 promotes K63-linked ubiquitination of FSP1 at K322 and K366 residues, which is essential for FSP1 plasma membrane translocation and its ferroptosis-suppressing function in cancer cells. Co-IP, K63 ubiquitination assay, K322/K366 site mutagenesis, membrane fractionation, ferroptosis assay Advanced science Medium 37587773
2023 Mycobacterium tuberculosis infection promotes TRIM21-mediated proteasomal degradation of HERC2 (an E3 ligase of NCOA4) via p38/AKT1-dependent phosphorylation, stabilizing NCOA4 and enhancing NCOA4-mediated ferritin degradation (ferritinophagy) to increase iron bioavailability for intracellular Mtb growth. Co-IP, ubiquitination assay, NCOA4 KO myeloid cells, macrophage infection model, mouse Mtb model The Journal of clinical investigation Medium 37066876
2023 ERK2 phosphorylates TRIM21 at Threonine 396 (T396) in KRAS-mutant CRC, disrupting TRIM21's interaction with c-Myc and preventing TRIM21-mediated K63-linked ubiquitination of c-Myc at K148 (which targets c-Myc for autophagic degradation), thereby promoting glycolysis and regorafenib resistance. Co-IP, ubiquitination assay, K148 and T396 site mutagenesis, autophagy assay, ERK2 kinase assay, xenograft models Proceedings of the National Academy of Sciences of the United States of America High 39388269
2023 TRIM21 promotes K48-linked ubiquitination and degradation of PEPCK1 and FASN through direct protein-protein interaction, regulating hepatic glucose and lipid metabolism in type 2 diabetes. Overexpression of PEPCK1 and FASN abolished the beneficial metabolic effects of TRIM21 overexpression. Co-IP, ubiquitination assay, hepatic overexpression/KD in diabetic mice, rescue with PEPCK1/FASN OE Cellular and molecular life sciences Medium 37249651
2023 TRIM21 ubiquitinates and degrades ChREBP, SREBP1, ACC1, FASN, and A1CF (lipogenic regulators), reducing de novo lipogenesis and fructose metabolism in NASH liver. TRIM21 is induced synergistically by TNF-α and fatty acids. Co-IP, ubiquitination assay, TRIM21 KO mice NASH model, hepatic lipid/metabolic assays JCI insight Medium 37937648
2023 TRIM21 directly interacts with and mediates K48-linked ubiquitination of TIF1γ at K5 in the nucleus, leading to TIF1γ degradation, reduced TIF1γ-mediated suppression, and increased nuclear K63-linked ubiquitination of β-catenin promoting its nuclear translocation in glioblastoma. TMT/MS substrate screen, Co-IP, luciferase reporter assay, domain deletion, K5 mutagenesis, in vivo siRNA Theranostics Medium 37771771
2023 TRIM21 interacts with ERK1/2 through its PRY-SPRY domain and catalyzes K27-linked ubiquitination of ERK1/2, which promotes MEK1/2-ERK1/2 interaction and ERK1/2 phosphorylation; however, excess TRIM21 suppresses ERK1/2 phosphorylation via negative feedback pathways. CRISPR screen, Co-IP, domain deletion (PRY-SPRY), ubiquitination assay, NanoBiT interaction assay Neuro-oncology Medium 39533840
2023 TRIM21 and TRIM8 mutually degrade each other via K48-linked ubiquitination through direct interaction, establishing a homeostatic balance between these two E3 ligases in lung and renal cancer cells. Co-IP, ubiquitination assay, expression correlation in clinical specimens Oncogene Medium 37914816
2023 Cytosolic antibody receptor TRIM21 is required for Ab-mediated protection against tau pathology in mice; tau-Ab complexes are internalized to the cytosol of neurons, enabling TRIM21 engagement and protection against seeded aggregation. Ab-mediated protection is lost in TRIM21 KO mice. TRIM21 KO mice, neuronal cell models, tau seeding assays, passive Ab transfer, in vivo tau pathology models Science High 36996217
2023 TRIM21 promotes K27-linked polyubiquitination of MAVS to regulate innate immunity (replicated finding from 2018); TRIM21 also regulates ISG12a via polyubiquitination, facilitating ISG12a translocation to mitochondria, caspase 3 activation, and GSDME cleavage leading to virus-induced pyroptosis. Co-IP, ubiquitination assay, mitochondrial fractionation, caspase 3 activation, GSDME cleavage assay Journal of immunology Medium 36426955
2023 TRIM21 promotes K63-linked ubiquitination of PD-1 at K233, stabilizing PD-1 by antagonizing its K48-linked ubiquitination and degradation. TRIM21 KO decreases PD-1 expression and enhances CD8+ T cell activation and anti-tumor immunity. Co-IP, K233 mutagenesis, K48 vs K63 ubiquitination linkage assay, TRIM21 KO T cells, CAR-T efficacy assay Molecular therapy Medium 39905727
2023 A TRIM21-based bioPROTAC (VHH antibody fused to TRIM21) can degrade endogenous HuR, and HuR degradation reverses tumour-promoting properties of cancer cells in vivo, establishing proof-of-concept for TRIM21-based targeted protein degradation. VHH-TRIM21 fusion construct, endogenous HuR degradation assay, proteomic analysis, in vivo xenograft Nature communications High 37925433
2023 TRIM21-dependent target protein ubiquitination (on the target rather than TRIM21 itself) is required for Trim-Away degradation. Chemical methylation of all TRIM21 lysines did not affect degradation, but deletion of all target lysines abolished ubiquitination and proteasomal degradation of target proteins in Xenopus egg extracts. Cell-free Xenopus egg extract system, chemical methylation of TRIM21, target lysine deletion, proteasomal degradation assay Cell reports High 36807144
2024 (S)-ACE-OH (acepromazine metabolite) acts as a molecular glue inducing interaction between TRIM21 and NUP98, leading to degradation of nuclear pore proteins. Substrate-induced clustering is required for TRIM21 activation, enabling selective degradation of multimeric proteins while sparing monomeric forms. Molecular glue screen, Co-IP, proteomics, nuclear pore integrity assay, PROTAC functionalization Cell High 39488207
2024 USP28 deubiquitinates and stabilizes TRIM21 (identified by Co-IP/MS), and the USP28-TRIM21 axis negatively regulates Nrf2 antioxidant response in cardiomyocytes, increasing oxidative stress and promoting cardiac hypertrophy. Co-IP/MS substrate screen, USP28 cardiomyocyte-specific KO mice, Ang II/TAC models, Nrf2 pathway assay Theranostics Medium 39431010
2024 TRIM21 interacts with EPHX1 via its SPRY domain and promotes K33- and K48-linked ubiquitination of EPHX1 at K105, leading to its degradation and inhibition of arachidonic acid metabolism in pancreatic cancer. Proteomics, ubiquitomics, LC-MS/MS, SPRY domain deletion, K105 mutagenesis, lipidomics Advanced science Medium 39739616
2024 EGFR activation induces c-Src-mediated CD47 Y288 phosphorylation, which inhibits TRIM21-CD47 interaction, thereby abrogating TRIM21-mediated K99/102 polyubiquitylation and degradation of CD47. CD47 Y288F knock-in reduces CD47 expression and increases macrophage phagocytosis. Co-IP, site mutagenesis (Y288F, K99/102R knock-in), ubiquitination assay, phagocytosis assay, brain tumor mouse model Advanced science Medium 37541303
2024 TRIM21 mediates K48-linked ubiquitination of METTL3 at K459, leading to proteasomal degradation of METTL3, which promotes ferroptosis by destabilizing SLC7A11 mRNA in pancreatic cancer. Co-IP, K459 mutagenesis, ubiquitination assay, SLC7A11 mRNA stability, ferroptosis assay Cell death & disease Medium 40175350
2025 Small-molecule ligands to TRIM21 (identified by DEL technology) induce degradation of NUP155 (and secondarily GLE1) via the ubiquitin-proteasome system in a TRIM21-dependent manner, impairing nuclear envelope integrity. Crystal structures of ligand-TRIM21 interaction were determined. DEL screening, crystallography, proteomics, TRIM21 KO rescue, ubiquitin-proteasome pathway assay, immunofluorescence ACS chemical biology High 40247740
2002 Ro52/TRIM21 is mono-ubiquitinated in cells, and also undergoes poly-ubiquitination, suggesting regulation by the ubiquitin-proteasome pathway. The biological relevance of mono-ubiquitination was not defined in this study. Immunoprecipitation, Western blot with ubiquitin antibodies Biochemical and biophysical research communications Low 12127959
2005 The RING-B-box-coiled-coil (RBCC) region of Ro52/TRIM21 requires Zn2+ for folding, with the linker between RING and B-box motifs crucial for full folding. The coiled-coil region (aa 200-239 leucine zipper) harbors conformationally dependent autoepitopes associated with congenital heart block. Fluorescence/CD spectroscopy, MALDI-TOF proteolysis, peptide synthesis, Zn2+ binding analysis The Journal of biological chemistry Medium 15964842
2008 Interferon-alpha induces upregulation of Ro52/TRIM21 protein and its translocation from cytoplasm to nucleus in HeLa and B cells, preceding IFN-α-induced apoptotic cell death. Monoclonal antibodies to different TRIM21 domains, Western blot, RT-PCR, immunofluorescence, caspase-3/TUNEL staining Journal of clinical immunology Medium 18071879
2014 TRIM21 is recruited to intracellular Salmonella enterica in epithelial cells early in infection through binding to opsonizing antibodies (not directly to bacteria). Bacterial restriction is dependent on TRIM21 and antibody opsonization, and TRIM21 co-localizes with autophagosomal marker LC3. Immunofluorescence co-localization, TRIM21 KD, bacterial restriction assay, autophagy marker staining Pathogens and disease Medium 24920099
2021 TRIM21 dysfunction in B cells leads to elevated IRF5 protein expression (due to reduced TRIM21-mediated ubiquitylation of IRF5), which promotes plasmablast differentiation and immunoglobulin production, contributing to SLE pathogenesis. Trim21-deficient MRL/lpr mice, Western blot for IRF5, B cell differentiation assay, Ab production assay Frontiers in immunology Medium 32117252

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
2008 TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved. Proceedings of the National Academy of Sciences of the United States of America 163 18420815
2010 Host cell invasion and virulence mediated by Candida albicans Ssa1. PLoS pathogens 160 21085601
2017 Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proceedings of the National Academy of Sciences of the United States of America 149 28049840
2012 The immunobiology of Ro52 (TRIM21) in autoimmunity: a critical review. Journal of autoimmunity 145 22402340
2018 TRIM21 Promotes Innate Immune Response to RNA Viral Infection through Lys27-Linked Polyubiquitination of MAVS. Journal of virology 134 29743353
2003 Candida albicans Ssa1/2p is the cell envelope binding protein for human salivary histatin 5. The Journal of biological chemistry 132 12761219
2021 Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin. EBioMedicine 121 34233258
2019 TRIM21-From Intracellular Immunity to Therapy. Frontiers in immunology 117 31555278
2023 TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models. Nature communications 109 36797289
2008 Interferon-alpha induces up-regulation and nuclear translocation of the Ro52 autoantigen as detected by a panel of novel Ro52-specific monoclonal antibodies. Journal of clinical immunology 104 18071879
2000 Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block. European journal of immunology 97 11069058
2023 UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders. Cell metabolism 92 37343564
2023 Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules. Autophagy 90 36692217
2015 TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. Immunological reviews 86 26497531
2020 HPV E7 inhibits cell pyroptosis by promoting TRIM21-mediated degradation and ubiquitination of the IFI16 inflammasome. International journal of biological sciences 79 33061806
2021 TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease. Frontiers in immunology 78 34552597
2023 TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury. Life sciences 69 36958437
2021 TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization. Cell death and differentiation 69 34511601
2024 Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders. Cell 66 39488207
2008 Biochemical and biophysical characterization of a chimeric TRIM21-TRIM5alpha protein. Journal of virology 61 18799572
2023 The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer. The Journal of clinical investigation 58 36749630
2020 Viral nucleoprotein antibodies activate TRIM21 and induce T cell immunity. The EMBO journal 58 33258165
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) 56 36353796
2023 Cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy in mouse models. Science (New York, N.Y.) 54 36996217
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) 54 37541303
2009 High Ro52 expression in spontaneous and UV-induced cutaneous inflammation. The Journal of investigative dermatology 54 19194477
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
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 52 36380368
2023 TRIM21 deficiency protects against atrial inflammation and remodeling post myocardial infarction by attenuating oxidative stress. Redox biology 49 36996623
2020 The E3 Ubiquitin Ligase TRIM21 Promotes HBV DNA Polymerase Degradation. Viruses 49 32245233
2023 TRIM21-Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 47 37587773
2021 TRIM21 Is Decreased in Colitis-associated Cancer and Negatively Regulates Epithelial Carcinogenesis. Inflammatory bowel diseases 47 32860065
2023 UBE2S interacting with TRIM21 mediates the K11-linked ubiquitination of LPP to promote the lymphatic metastasis of bladder cancer. Cell death & disease 46 37422473
2022 Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer. Molecular cancer 44 36376892
2023 Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth. The Journal of clinical investigation 43 37066876
2023 BCKDK regulates breast cancer cell adhesion and tumor metastasis by inhibiting TRIM21 ubiquitinate talin1. Cell death & disease 41 37460470
2023 Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling. Bone research 40 37884520
2023 TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer. Cell death & disease 39 38123542
2021 E3 ubiquitin ligase TRIM21 restricts hepatitis B virus replication by targeting HBx for proteasomal degradation. Antiviral research 39 34097931
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
2023 TRIM21 attenuates renal carcinoma lipogenesis and malignancy by regulating SREBF1 protein stability. Journal of experimental & clinical cancer research : CR 38 36694250
2020 TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis. Frontiers in immunology 38 32117252
1996 The refolding activity of the yeast heat shock proteins Ssa1 and Ssa2 defines their role in protein translocation. The Journal of cell biology 37 8947547
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 34 38040417
2016 Coordinated Neutralization and Immune Activation by the Cytosolic Antibody Receptor TRIM21. Journal of virology 33 26937031
2014 Antibody- and TRIM21-dependent intracellular restriction of Salmonella enterica. Pathogens and disease 33 24920099
2023 TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2. Cell chemical biology 32 37354905
2023 Multiple Roles of TRIM21 in Virus Infection. International journal of molecular sciences 31 36675197
2020 HDAC6 regulates antibody-dependent intracellular neutralization of viruses via deacetylation of TRIM21. The Journal of biological chemistry 31 32796032
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 30 39388269
2023 A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation. Nature communications 30 37925433
2022 Potent TRIM21 and complement-dependent intracellular antiviral immunity requires the IgG3 hinge. Science immunology 28 35486676
2021 LncTRPM2-AS inhibits TRIM21-mediated TRPM2 ubiquitination and prevents autophagy-induced apoptosis of macrophages in asthma. Cell death & disease 28 34903714
2017 Enhancement of Th1/Th17 inflammation by TRIM21 in Behçet's disease. Scientific reports 28 28592884
2023 E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma. Theranostics 27 37771771
2009 Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice. The Journal of experimental medicine 27 19635865
2019 Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners. Cells 26 31540324
2002 Ubiquitination of Ro52 autoantigen. Biochemical and biophysical research communications 26 12127959
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) 25 38357830
2023 USP25 promotes hepatocellular carcinoma progression by interacting with TRIM21 via the Wnt/β-catenin signaling pathway. Chinese medical journal 24 37439386
2022 Functional skewing of TRIM21-SIRT5 interplay dictates IL-1β production in DSS-induced colitis. EMBO reports 24 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.) 23 38130019
2021 The molecular mechanisms that drive intracellular neutralization by the antibody-receptor and RING E3 ligase TRIM21. Seminars in cell & developmental biology 22 34823983
2005 Structural organization and Zn2+-dependent subdomain interactions involving autoantigenic epitopes in the Ring-B-box-coiled-coil (RBCC) region of Ro52. The Journal of biological chemistry 22 15964842
2024 Trim21-mediated CCT2 ubiquitination suppresses malignant progression and promotes CD4+T cell activation in breast cancer. Cell death & disease 21 39079960
2024 TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1-Mediated Arachidonic Acid Metabolism. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 21 39739616
2023 TRIM21-dependent target protein ubiquitination mediates cell-free Trim-Away. Cell reports 21 36807144
2023 EDARADD promotes colon cancer progression by suppressing E3 ligase Trim21-mediated ubiquitination and degradation of Snail. Cancer letters 21 37838280
2024 SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation. Cancer letters 20 38360141
2023 TRIM21 promotes ubiquitination of SARS-CoV-2 nucleocapsid protein to regulate innate immunity. Journal of medical virology 20 37185839
2023 The interconnected roles of TRIM21/Ro52 in systemic lupus erythematosus, primary Sjögren's syndrome, cancers, and cancer metabolism. Cancer cell international 20 37993883
2004 Cloning and characterization of two human Ro52-specific monoclonal autoantibodies directed towards a domain associated with congenital heart block. Journal of autoimmunity 20 14987746
2018 Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus. Modern rheumatology 18 29385873
2023 TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN. Cellular and molecular life sciences : CMLS 17 37249651
2022 Phosphorylation-Induced Ubiquitination and Degradation of PXR through CDK2-TRIM21 Axis. Cells 17 35053380
2014 Intracellular antibody immunity and the cytosolic Fc receptor TRIM21. Current topics in microbiology and immunology 17 25116095
2005 Structurally derived mutations define congenital heart block-related epitopes within the 200-239 amino acid stretch of the Ro52 protein. Scandinavian journal of immunology 17 15683447
2024 NCAPH, ubiquitinated by TRIM21, promotes cell proliferation by inhibiting autophagy of cervical cancer through AKT/mTOR dependent signaling. Cell death & disease 16 39103348
2023 Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators. JCI insight 16 37937648
2022 TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination of ISG12a. Journal of immunology (Baltimore, Md. : 1950) 16 36426955
2020 Negative feedback regulation by HuR controls TRIM21 expression and function in response to UV radiation. Scientific reports 16 32678213
2024 Cardiomyocyte-derived USP28 negatively regulates antioxidant response and promotes cardiac hypertrophy via deubiquitinating TRIM21. Theranostics 15 39431010
2015 Serological epitope profile of anti-Ro52-positive patients with systemic autoimmune rheumatic diseases. Arthritis research & therapy 15 26673754
2025 Chemically Induced Nuclear Pore Complex Protein Degradation via TRIM21. ACS chemical biology 14 40247740
2024 TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors. British journal of cancer 14 38182686
2024 STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 39527690
2024 MDM4 inhibits ferroptosis in p53 mutant colon cancer via regulating TRIM21/GPX4 expression. Cell death & disease 14 39543140
2023 Berberine promotes IGF2BP3 ubiquitination by TRIM21 to induce G1/S phase arrest in colorectal cancer cells. Chemico-biological interactions 14 36822301
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
1995 Efficient translation of an SSA1-derived heat-shock mRNA in yeast cells limited for cap-binding protein and eIF-4F. Molecular & general genetics : MGG 14 7700235
2025 TRIM21-mediated METTL3 degradation promotes PDAC ferroptosis and enhances the efficacy of Anti-PD-1 immunotherapy. Cell death & disease 13 40175350
2022 MICALL2 as a substrate of ubiquitinase TRIM21 regulates tumorigenesis of colorectal cancer. Cell communication and signaling : CCS 13 36307841
2016 Surveillance for Intracellular Antibody by Cytosolic Fc Receptor TRIM21. Antibodies (Basel, Switzerland) 13 31558002
2025 TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas. Neuro-oncology 12 39533840
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
2024 TNKS1BP1 facilitates ubiquitination of CNOT4 by TRIM21 to promote hepatocellular carcinoma progression and immune evasion. Cell death & disease 12 39019859
2024 TRIM21-mediated ubiquitination of SQSTM1/p62 abolishes its Ser403 phosphorylation and enhances palmitic acid cytotoxicity. Autophagy 12 39172027
2023 Mutual regulation between TRIM21 and TRIM8 via K48-linked ubiquitination. Oncogene 12 37914816
2022 Anti-Ro52/TRIM21 serological subsets identify differential clinical and laboratory parameters. Clinical rheumatology 12 35871174