TRIM21

Summary

TRIM21 (tripartite motif containing 21, HGNC:11312) is a protein-coding gene on chromosome 11p15.4, encoding E3 ubiquitin-protein ligase TRIM21 (P19474). E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2.

This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined.

Source: NCBI Gene 6737 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 56 total
• MANE Select transcript: NM_003141

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11312
Approved symbol	TRIM21
Name	tripartite motif containing 21
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	TRIM21/Ro52, RNF81, RO52
Ensembl gene	ENSG00000132109
Ensembl biotype	protein_coding
OMIM	109092
Entrez	6737

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000254436, ENST00000533692, ENST00000881224, ENST00000934674, ENST00000962553

RefSeq mRNA: 1 — MANE Select: NM_003141 NM_003141

CCDS: CCDS44525

Canonical transcript exons

ENST00000254436 — 7 exons

Exon	Start	End
ENSE00000903567	4390002	4390458
ENSE00000903568	4389654	4389749
ENSE00000903569	4388300	4388530
ENSE00000903570	4386157	4386257
ENSE00001120468	4393633	4393702
ENSE00001120479	4384897	4385853
ENSE00001700049	4386968	4386990

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 94.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.6109 / max 371.1609, expressed in 1747 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118328	9.6109	1747

Top tissues by expression

274 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.60	gold quality
leukocyte	CL:0000738	91.92	gold quality
monocyte	CL:0000576	91.80	gold quality
mononuclear cell	CL:0000842	91.56	gold quality
blood	UBERON:0000178	91.21	gold quality
mucosa of transverse colon	UBERON:0004991	90.04	gold quality
spleen	UBERON:0002106	88.33	gold quality
rectum	UBERON:0001052	86.68	gold quality
colonic epithelium	UBERON:0000397	86.02	gold quality
apex of heart	UBERON:0002098	85.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.69	gold quality
descending thoracic aorta	UBERON:0002345	85.24	gold quality
transverse colon	UBERON:0001157	84.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.72	gold quality
ileal mucosa	UBERON:0000331	84.71	gold quality
upper lobe of left lung	UBERON:0008952	84.70	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.59	gold quality
lower esophagus	UBERON:0013473	84.57	gold quality
vermiform appendix	UBERON:0001154	84.34	gold quality
lymph node	UBERON:0000029	84.18	gold quality
small intestine	UBERON:0002108	84.17	gold quality
calcaneal tendon	UBERON:0003701	84.17	gold quality
gall bladder	UBERON:0002110	84.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.97	gold quality
upper lobe of lung	UBERON:0008948	83.96	gold quality
right coronary artery	UBERON:0001625	83.83	gold quality
mucosa of stomach	UBERON:0001199	83.74	gold quality
body of stomach	UBERON:0001161	83.71	gold quality
right adrenal gland	UBERON:0001233	83.60	gold quality
right lobe of liver	UBERON:0001114	83.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7037	yes	182.92
E-ANND-3	yes	3.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
JUN	Activation

Upstream regulators (CollecTRI, top): ESR1, IRF1, IRF2, IRF4, IRF8, NFKB1, RELA

miRNA regulators (miRDB)

35 targeting TRIM21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-6529-5P	97.85	66.47	673
HSA-MIR-6511A-3P	97.60	66.61	713
HSA-MIR-6511B-3P	97.60	66.61	713
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-4474-3P	96.97	65.87	870

Literature-anchored findings (GeneRIF, showing 40)

• that Ro52 may be downregulated by the ubiquitin-proteasome pathway in vivo (PMID:12127959)
• First evidence is provided for the involvement of SS-A in CD28-induced production of IL-2, which is critical in the pathophysiology of autoimmune diseases such as Sjogren’s syndrome and systemic lupus erythematosus. (PMID:12646630)
• Immunologic analysis of the stable protein regions with sera from patients with Sjogren’s syndrome shows that immunodominant epitopes to a large extent are localized in the structurally stable parts of Ro52 (PMID:15916807)
• Reactivity to p200 is a dominant but not uniform anti-Ro 52 response in women whose children have congenital heart block (PMID:16200587)
• Ro52 is a RING-finger-type E3 ubiquitin ligase. (PMID:16297862)
• These results suggest that UnpEL colocalizes with the unubiquitinated form of Ro52 to the cytoplasmic rod-like structures. (PMID:16316627)
• Antibody subsets may represent important biomarkers to predict a complication in pregnant lupus women with Ro52 antibodies. (PMID:16356190)
• analysis of subcellular location and function of Ro52beta (PMID:16403452)
• Ro52 and UnpEL transregulate each other by ubiquitination and deubiquitination (PMID:16472766)
• Presence of serum tripartite motif-containing 21 antibodies in patients with esophageal squamous cell carcinoma (PMID:16630135)
• Increased expression of Ro52 in patients may be directly involved in the reduced cellular proliferation and increased apoptotic cell death observed in Sjogren’s syndrome and systemic lupus erythematosus. (PMID:16670339)
• heterologous RING, B-box 2, and CC domains from related TRIM proteins can functionally substitute for TRIM5alpha(rh) domains. (PMID:16775307)
• These data suggest a key role for Ro52 RING finger protein in the regulation of p27 degradation and S-phase progression in mammalian cells. (PMID:16880511)
• Nuclear injury and the translocation of SSA/Ro and SSB/La antigens to the fetal cardiocyte plasma membrane were common downstream events of Fas and TNF receptor ligation. (PMID:16906225)
• The data suggest that the normal function of TRIM21 involves regulation of IgG functions and that TRIM/B30.2 molecules may have broader and unsuspected roles in innate immunity, beyond that of retroviral restriction. (PMID:17118455)
• A TRIM21 antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease (PMID:17400754)
• Increased Ro/SSA 60 and La/SSB mRNA expression in minor salivary glands in primary Sjogren’s syndrome (pSS) suggest that these 2 autoantigens, but not Ro/SSA 52, are involved in tissue-specific autoimmune response in pSS. (PMID:17552056)
• Plays a role in mediating the anti-proliferative or pro-apoptotic effects of autoimmune-related cytokine interferon-alpha. (PMID:18071879)
• results obtained from Ro52 are extendable to the entire TRIM protein family (PMID:18272178)
• These data support the novel notion of the association between Ro52 with hDCP2 protein in cytoplasmic p-bodies, playing a role in mRNA metabolism in response to cellular stimulation. (PMID:18361920)
• TRIM21 is a previously undescribed type of IgG receptor based on a non-Ig scaffold whose interaction at the fundamental level-structural, thermodynamic, and kinetic-is evolutionarily conserved. (PMID:18420815)
• demonstrates a novel role for Ro52 in turning off and thus limiting IRF3-dependent type I IFN production by targeting the transcription factor for polyubiquitination and subsequent proteasomal degradation (PMID:18641315)
• Ro52 has both cytoplasmic and nuclear substrates, and mediates ubiquitination through UBE2D1 in the cytoplasm and through UBE2E1 in the nucleus. (PMID:18845142)
• rs660 polymorphism is a marker of efficiency of tolerance induction in early childhood and immune competence development to RBC antigens in SCD patients of pre-teen/teen age. (PMID:19201475)
• TRIM21 is an essential modulator of interferon regulatory factor 3 (IRF3) stability that positively regulates the strength and duration of primary antiviral response. (PMID:19265157)
• Ro52 down-regulates Tax-induced NF-kappaB signalling by monoubiquitinating IKKbeta and by reducing the level of Tax (PMID:19675099)
• Importantly, the Ro52 cytoplasmic bodies are highly motile and are located along the microtubule network. These results suggest that the Ro52 cytoplasmic bodies are unidentified structures that are transported along the microtubule network. (PMID:20013343)
• 60 kD Ro and nRNP A frequently initiate human lupus autoimmunity (PMID:20224770)
• Ro52-mediated monoubiquitination is involved in the subcellular translocation of active IKK beta to autophagosomes. (PMID:20627395)
• Results suggest that Ro52-mediated ubiquitination promotes the degradation of IRF7 following TLR7 and TLR9 stimulation. (PMID:20668674)
• Cells possess a cytosolic IgG receptor, tripartite motif-containing 21 (TRIM21), which binds to antibodies with a higher affinity than any other IgG receptor in the human body. (PMID:21045130)
• FADD and TRIM21 together negatively regulate the late IFN-alpha pathway in response to viral infection. (PMID:21183682)
• anti-Ro52 autoantibodies binding the RING domain of Ro52 may be actively involved in the pathogenesis of rheumatic autoimmune disease by inhibiting Ro52-mediated ubiquitination. (PMID:21862588)
• These findings shed light on a new physiological role for Ro52 that is important to intracellular immunity. (PMID:22178074)
• data suggest that Ro52/SSA is involved in death receptor-mediated apoptosis by regulating c-FLIP(L) (PMID:22288650)
• Anti-TRIM21 antibodies were the second most common autoantibodies in this systemic sclerosis cohort. (PMID:22394602)
• analysis of a novel role for tyrosine phosphorylation in regulating the interaction with IRF3 and the activity of TRIM21 downstream of TLR3 and TLR4 (PMID:22479513)
• The direct interaction between TRIM21 and neutralizing antibody is essential, as single-point mutations within the TRIM21-binding site in the Fc region of a potently neutralizing antibody impair virus neutralization. (PMID:22647693)
• Anti-Ro52 antibodies were closely associated with the main clinical, histopathological and immunological features of primary Sjogren’s syndrome. (PMID:22704838)
• This retrospective study supports the routine distinction of anti-SSA/Ro60 and anti-Ro52/TRIM21 due to their different clinical associations. (PMID:23039326)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Trim21	ENSMUSG00000030966
rattus_norvegicus	Trim21	ENSRNOG00000018517

Paralogs (80): MID2 (ENSG00000080561), TRIM9 (ENSG00000100505), MID1 (ENSG00000101871), MEFV (ENSG00000103313), TRIM35 (ENSG00000104228), TRIM14 (ENSG00000106785), TRIM37 (ENSG00000108395), TRIM2 (ENSG00000109654), TRIM3 (ENSG00000110171), TRIM38 (ENSG00000112343), TRIM62 (ENSG00000116525), TRIM67 (ENSG00000119283), TRIM32 (ENSG00000119401), BSPRY (ENSG00000119411), TRIM25 (ENSG00000121060), TRIM6 (ENSG00000121236), TRIM24 (ENSG00000122779), TRIM51 (ENSG00000124900), TRIM28 (ENSG00000130726), TRIM5 (ENSG00000132256), TRIM22 (ENSG00000132274), TRIM47 (ENSG00000132481), TRIM45 (ENSG00000134253), TRIM29 (ENSG00000137699), TRIM54 (ENSG00000138100), PML (ENSG00000140464), TRIM65 (ENSG00000141569), TRIM43B (ENSG00000144010), TRIM43 (ENSG00000144015), TRIM7 (ENSG00000146054), TRIM41 (ENSG00000146063), TRIM50 (ENSG00000146755), TRIM4 (ENSG00000146833), TRIM55 (ENSG00000147573), TRIM48 (ENSG00000150244), TRIM36 (ENSG00000152503), TRIM11 (ENSG00000154370), TRIM74 (ENSG00000155428), TRIM42 (ENSG00000155890), TRIM63 (ENSG00000158022)

Protein

Protein identifiers

E3 ubiquitin-protein ligase TRIM21 — P19474 (reviewed: P19474)

Alternative names: 52 kDa Ro protein, 52 kDa ribonucleoprotein autoantigen Ro/SS-A, RING finger protein 81, Ro(SS-A), Sjoegren syndrome type A antigen, Tripartite motif-containing protein 21

All UniProt accessions (2): P19474, H0YDP8

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B (‘Thr-187’ phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by catalyzing polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Also regulates autophagy through FIP200/RB1CC1 ubiquitination and subsequent decreased protein stability. Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through ‘Lys-63’-linked ubiquitination of NMI. During viral infection, promotes cell pyroptosis by mediating ‘Lys-6’-linked ubiquitination of ISG12a/IFI27, facilitating its translocation into the mitochondria and subsequent CASP3 activation. When up-regulated through the IFN/JAK/STAT signaling pathway, promotes ‘Lys-27’-linked ubiquitination of MAVS, leading to the recruitment of TBK1 and up-regulation of innate immunity. Mediates ‘Lys-63’-linked polyubiquitination of G3BP1 in response to heat shock, leading to stress granule disassembly.

Subunit / interactions. Homotrimer. Interacts (via C-terminus) with IRF8 (via C-terminus). Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Interacts with CALR, CUL1, FBXW11, HSPA5, IKBKB, IRF3, SKP1 and VCP. Interacts with SKP2; the interaction with SKP2 does not depend on an intact F-box domain. Interacts (via N-terminus and C-terminus) with DCP2 (via N-terminus and C-terminus). Interacts with ULK1, BECN1 and with ATG8 family members, including GABARAP, GABARAPL1, GABARAPL2 and MAP1LC3C/LC3C. Interacts with TRIM21 and SQSTM1/sequestosome 1. Interacts with IRF3. Interacts (via the SPRY domain) with NMI (via coiled-coil domain); the interaction promotes ‘Lys-63’-linked ubiquitination of NMI. Interacts with IFI35 and NMI; the interaction facilitates NMI-IFI35 complex formation. (Microbial infection) Interacts (via B30.2/SPRY domain) with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction activates NFE2L2-mediated transcriptional activation of antioxidant genes.

Subcellular location. Cytoplasm. Cytoplasmic vesicle. Autophagosome. Nucleus. P-body. Stress granule.

Tissue specificity. Isoform 1 and isoform 2 are expressed in fetal and adult heart and fetal lung.

Post-translational modifications. Autoubiquitinated; does not lead to its proteasomal degradation. Deubiquitinated by USP4; leading to its stabilization.

Domain organisation. The coiled-coil is necessary for the cytoplasmic localization. The RING-type zinc finger is necessary for ubiquitination and for the IRF3-driven interferon beta promoter activity. Interacts with SKP2 and CUL1 in a RING finger-independent manner. The RING-type zinc finger is necessary for ubiquitination of NMI. The B30.2/SPRY domain is necessary for the cytoplasmic localization, the interaction with IRF3 and for the IRF3-driven interferon beta promoter activity. The B30.2/SPRY domain is necessary for the interaction with NMI.

Induction. Up-regulated by isoform 2 of XBP1. Up-regulated by IFNG/interferon-gamma, with a peak after 2-4 hours of treatment in monocytes/macrophages.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the TRIM/RBCC family.

Isoforms (2)

UniProt ID	Names	Canonical?
P19474-1	1, Ro52alpha, 52alpha	yes
P19474-2	2, Ro52beta, 52beta

RefSeq proteins (1): NP_003132* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000315	Znf_B-box	Domain
IPR001841	Znf_RING	Domain
IPR001870	B30.2/SPRY	Domain
IPR003613	Ubox_domain	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	Domain
IPR006574	PRY	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR020457	Znf_B-box_chordata	Domain
IPR035831	PRY/SPRY_TRIM21	Domain
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR050143	TRIM/RBCC	Family

Pfam: PF00097, PF00622, PF00643, PF13765

UniProt features (60 total): strand 22, turn 10, helix 6, sequence conflict 5, sequence variant 4, binding site 4, mutagenesis site 2, zinc finger region 2, chain 1, domain 1, splice variant 1, coiled-coil region 1, modified residue 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
9PLM	X-RAY DIFFRACTION	1.32
9QBA	X-RAY DIFFRACTION	1.45
9II5	X-RAY DIFFRACTION	1.49
8Y58	X-RAY DIFFRACTION	1.6
9PLL	X-RAY DIFFRACTION	1.6
8Y5B	X-RAY DIFFRACTION	1.74
8Y59	X-RAY DIFFRACTION	1.89
5OLM	X-RAY DIFFRACTION	1.95
9M3N	X-RAY DIFFRACTION	2.08
9EK5	X-RAY DIFFRACTION	2.1
9Q9P	X-RAY DIFFRACTION	2.1
7BBD	X-RAY DIFFRACTION	2.2
8A58	X-RAY DIFFRACTION	2.25
9Q9Q	X-RAY DIFFRACTION	2.25
9Q9R	X-RAY DIFFRACTION	2.33
2IWG	X-RAY DIFFRACTION	2.35
9Q9O	X-RAY DIFFRACTION	2.46
6S53	X-RAY DIFFRACTION	2.8
6FGA	X-RAY DIFFRACTION	2.82
5JPX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19474-F1	90.98	0.77

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 92; 95; 114; 120

Post-translational modifications (1): 266

Mutagenesis-validated functional residues (2):

Position	Phenotype
16	loss of e3 ubiquitin-protein ligase activity. does not inhibit nf-kappa-b-induced gene expression. loss of e3 ubiquitin-
31–33	loss of e3 ubiquitin-protein ligase activity; when associated with a-16.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1834941	STING mediated induction of host immune responses
R-HSA-3134975	Regulation of innate immune responses to cytosolic DNA
R-HSA-877300	Interferon gamma signaling
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-2262752	Cellular responses to stress
R-HSA-8953897	Cellular responses to stimuli
R-HSA-913531	Interferon Signaling
R-HSA-9711123	Cellular response to chemical stress
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 386 (showing top): GOBP_POSITIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PROTEIN_BINDING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (33): protein polyubiquitination (GO:0000209), protein monoubiquitination (GO:0006513), regulation of gene expression (GO:0010468), proteasomal protein catabolic process (GO:0010498), positive regulation of autophagy (GO:0010508), protein ubiquitination (GO:0016567), protein destabilization (GO:0031648), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), positive regulation of protein binding (GO:0032092), regulation of type I interferon production (GO:0032479), negative regulation of viral transcription (GO:0032897), response to type II interferon (GO:0034341), stress granule disassembly (GO:0035617), protein K27-linked ubiquitination (GO:0044314), suppression of viral release by host (GO:0044790), innate immune response (GO:0045087), positive regulation of cell cycle (GO:0045787), negative regulation of innate immune response (GO:0045824), positive regulation of viral entry into host cell (GO:0046598), protein autoubiquitination (GO:0051865), cellular response to chemical stress (GO:0062197), pyroptotic inflammatory response (GO:0070269), protein K63-linked ubiquitination (GO:0070534), protein K48-linked ubiquitination (GO:0070936), protein K6-linked ubiquitination (GO:0085020), negative regulation of protein deubiquitination (GO:0090086), antiviral innate immune response (GO:0140374), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), autophagosome assembly (GO:0000045), canonical NF-kappaB signal transduction (GO:0007249), stress granule assembly (GO:0034063), positive regulation of DNA-templated transcription (GO:0045893), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (10): DNA binding (GO:0003677), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), cytoplasmic vesicle (GO:0031410), ribonucleoprotein complex (GO:1990904), SCF ubiquitin ligase complex (GO:0019005)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Immune System	3
Cytosolic sensors of pathogen-associated DNA	2
Interferon Signaling	1
Cellular response to chemical stress	1
Class I MHC mediated antigen processing & presentation	1
Innate Immune System	1
Cellular responses to stimuli	1
Cytokine Signaling in Immune system	1
Cellular responses to stress	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	3
cellular anatomical structure	3
protein binding	2
innate immune response	2
nucleic acid binding	2
cytoplasmic ribonucleoprotein granule	2
cytoplasm	2
gene expression	1
regulation of macromolecule biosynthetic process	1
protein catabolic process	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
protein modification by small protein conjugation	1
regulation of protein stability	1
regulation of protein binding	1
positive regulation of binding	1
regulation of cytokine production	1
type I interferon production	1
viral transcription	1
regulation of viral transcription	1
negative regulation of viral process	1
response to cytokine	1
protein-RNA complex disassembly	1
organelle disassembly	1
protein polyubiquitination	1
defense response to virus	1
immune response	1
defense response to symbiont	1
cell cycle	1
positive regulation of cellular process	1
regulation of cell cycle	1
negative regulation of response to biotic stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of innate immune response	1
negative regulation of immune response	1
regulation of viral entry into host cell	1
symbiont entry into host cell	1
positive regulation by symbiont of entry into host	1

Protein interactions and networks

STRING

2336 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIM21	RO60	P10155	998
TRIM21	SSB	P05455	997
TRIM21	IRF3	Q14653	960
TRIM21	ERBB2	P04626	945
TRIM21	CDH1	P12830	912
TRIM21	EGFR	P00533	900
TRIM21	TRAT1	Q6PIZ9	899
TRIM21	HTN3	P15516	892
TRIM21	SNRNP70	P08621	848
TRIM21	USP4	Q13107	846
TRIM21	BBOX1	O75936	830
TRIM21	EXOSC10	Q01780	820
TRIM21	CENPB	P07199	815
TRIM21	CALR	P27797	815
TRIM21	DNAJB4	Q9UDY4	814

IntAct

257 interactions, top by confidence:

A	B	Type	Score
TRIM21	TRIM21	psi-mi:“MI:0915”(physical association)	0.810
TRIM21	UBE2I	psi-mi:“MI:0915”(physical association)	0.720
GRAP	TRIM21	psi-mi:“MI:0915”(physical association)	0.720
TXN2	TRIM21	psi-mi:“MI:0915”(physical association)	0.720
TRIM21	TXN2	psi-mi:“MI:0915”(physical association)	0.720
TRIM21	GRAP	psi-mi:“MI:0915”(physical association)	0.720
UBE2I	TRIM21	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	TRIM21	psi-mi:“MI:0403”(colocalization)	0.680
CFTR	TRIM21	psi-mi:“MI:0914”(association)	0.680
TRIM21	CFTR	psi-mi:“MI:0914”(association)	0.680
TRIM21	TRIM39	psi-mi:“MI:0915”(physical association)	0.670
TRIM39	TRIM21	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (1020): TRIM21 (Two-hybrid), TRIM21 (Two-hybrid), UBE2I (Two-hybrid), USP15 (Two-hybrid), GRAP (Two-hybrid), TXN2 (Two-hybrid), IGHV4-31 (Two-hybrid), TRIM39 (Two-hybrid), NIF3L1 (Two-hybrid), IRF5 (Affinity Capture-Western), IRF5 (Reconstituted Complex), TRIM21 (Affinity Capture-MS), TRIM21 (Affinity Capture-MS), TRIM21 (Affinity Capture-MS), TRIM21 (Affinity Capture-MS)

ESM2 similar proteins: A0JN74, A6NCK2, A6NGJ6, A6NI03, B1H278, K7N6K2, O00478, O00481, P14373, P19474, Q13410, Q1ACD5, Q1ACD6, Q1ACD7, Q1ACD8, Q1XHU0, Q2YEM8, Q2YEM9, Q3ZEE5, Q587N6, Q5C8T6, Q5C8T8, Q5C8U1, Q5D7I9, Q5D7J0, Q5D7J1, Q5NCC9, Q5R996, Q62158, Q6MFZ5, Q7YR33, Q7YRV4, Q80V85, Q8BGE7, Q8NG06, Q923T7, Q96BQ3, Q96F44, Q99PP6, Q99PQ2

Diamond homologs: A0A2P1BRP3, A0A2P1BRQ0, A0JN74, A0ZSK3, A0ZSK4, B1H278, O19085, O95361, P14373, P19474, Q02084, Q1XHU0, Q309B1, Q5R760, Q5R7W8, Q62158, Q62556, Q7KYR7, Q86WT6, Q8N7C3, Q8WVV5, Q91431, Q91453, Q96F44, Q98989, Q98993, Q99PP9, Q99PQ2, Q9C029, Q9HCM9, Q9JLN5, A0A3B3IT33, A6NCK2, A6NDI0, A6NGJ6, A6NI03, A6NLI5, B0BLU1, C9J1S8, I1YAP6

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
TRIM21	down-regulates	GMPS	ubiquitination
TRIM21	“down-regulates quantity by destabilization”	FASN	ubiquitination
Ub:E2	“up-regulates activity”	TRIM21	ubiquitination
TRIM21	“up-regulates quantity”	TRIM5	monoubiquitination
GNAO1	“up-regulates activity”	TRIM21	binding
TRIM21	“down-regulates activity”	SQSTM1	ubiquitination
TRIM21	“down-regulates quantity by destabilization”	IRF7	ubiquitination
TRIM21	“down-regulates quantity”	DDX41	ubiquitination
TRIM21	“down-regulates quantity”	IRF8	ubiquitination
TRIM21	“down-regulates quantity”	SHMT2	ubiquitination
GNAO1	down-regulates	TRIM21

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	5	24.5×	6e-04
protein deubiquitination	5	13.7×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

56 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1088 predictions. Top by Δscore:

Variant	Effect	Δscore
11:4385748:T:TA	donor_gain	1.0000
11:4385854:C:CC	acceptor_gain	1.0000
11:4386152:CTCAC:C	donor_loss	1.0000
11:4386153:TCA:T	donor_loss	1.0000
11:4386154:CA:C	donor_loss	1.0000
11:4386253:CACTC:C	acceptor_gain	1.0000
11:4386255:CTC:C	acceptor_gain	1.0000
11:4386257:CCTG:C	acceptor_loss	1.0000
11:4386258:C:CC	acceptor_gain	1.0000
11:4386259:T:A	acceptor_loss	1.0000
11:4388533:T:C	acceptor_gain	1.0000
11:4388536:G:GC	acceptor_gain	1.0000
11:4388541:A:T	acceptor_gain	1.0000
11:4389648:TCTTA:T	donor_loss	1.0000
11:4389649:CTTA:C	donor_loss	1.0000
11:4389650:TTA:T	donor_loss	1.0000
11:4389651:TA:T	donor_loss	1.0000
11:4389652:A:C	donor_loss	1.0000
11:4389653:C:CT	donor_loss	1.0000
11:4389747:CTC:C	acceptor_gain	1.0000
11:4389750:C:CC	acceptor_gain	1.0000
11:4389750:CT:C	acceptor_loss	1.0000
11:4390454:TTTGG:T	acceptor_gain	1.0000
11:4390455:TTGG:T	acceptor_gain	1.0000
11:4390456:TGG:T	acceptor_gain	1.0000
11:4390457:GG:G	acceptor_gain	1.0000
11:4390459:C:CC	acceptor_gain	1.0000
11:4392635:A:AC	donor_gain	1.0000
11:4392636:C:CC	donor_gain	1.0000
11:4392637:TTTTG:T	donor_gain	1.0000

AlphaMissense

3125 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:4385683:A:G	W344R	0.994
11:4385683:A:T	W344R	0.994
11:4385738:A:C	F325L	0.994
11:4385738:A:T	F325L	0.994
11:4385740:A:G	F325L	0.994
11:4385653:A:G	W354R	0.993
11:4385653:A:T	W354R	0.993
11:4390305:G:C	F35L	0.993
11:4390305:G:T	F35L	0.993
11:4390307:A:G	F35L	0.993
11:4385453:G:C	F420L	0.991
11:4385453:G:T	F420L	0.991
11:4385455:A:G	F420L	0.991
11:4385681:C:A	W344C	0.989
11:4385681:C:G	W344C	0.989
11:4390104:G:C	F102L	0.989
11:4390104:G:T	F102L	0.989
11:4390106:A:G	F102L	0.989
11:4390259:A:G	C51R	0.989
11:4390364:A:G	C16R	0.989
11:4385814:A:G	L300P	0.988
11:4390308:G:C	S34R	0.988
11:4390308:G:T	S34R	0.988
11:4390310:T:G	S34R	0.988
11:4385414:G:C	F433L	0.986
11:4385414:G:T	F433L	0.986
11:4385416:A:G	F433L	0.986
11:4390311:G:C	H33Q	0.986
11:4390311:G:T	H33Q	0.986
11:4385618:C:A	R365S	0.985

dbSNP variants (sampled 300 via entrez): RS1000177576 (11:4387836 A>G), RS1000202384 (11:4386012 C>G,T), RS1000274970 (11:4392887 A>G), RS1000284862 (11:4393161 A>G), RS1000378272 (11:4391093 A>T), RS1000471548 (11:4391495 A>G), RS1000853867 (11:4394979 T>A), RS1000864839 (11:4395371 A>G), RS1001445687 (11:4389041 T>C), RS1001557322 (11:4390765 A>G), RS1001684462 (11:4395671 A>T), RS1001997531 (11:4385718 A>G), RS1002048949 (11:4391020 G>T), RS1002728040 (11:4394638 C>T), RS1002821773 (11:4394901 C>T)

Disease associations

OMIM: gene MIM:109092 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004748_21	Lung cancer	8.000000e-06
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.3.2.27 RING-type E3 ubiquitin transferase

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases expression	4
Tetrachlorodibenzodioxin	increases expression	2
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
monomethylarsonous acid	affects expression	1
ICG 001	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Eucalyptol	decreases expression	1
Acetaminophen	decreases expression	1
Aspirin	decreases expression	1
Berberine	affects binding, increases reaction	1
Detergents	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Insecticides	increases expression	1
Ivermectin	decreases expression	1
Nickel	increases expression	1
Quercetin	increases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1IB	Abcam A-549 TRIM21 KO 2	Cancer cell line	Male
CVCL_B2QU	Abcam A-549 TRIM21 KO 1	Cancer cell line	Male
CVCL_D9UX	Ubigene HEK293 TRIM21 KO	Transformed cell line	Female
CVCL_E0S6	Ubigene HeLa TRIM21 KO	Cancer cell line	Female
CVCL_TT87	HAP1 TRIM21 (-) 1	Cancer cell line	Male
CVCL_TT88	HAP1 TRIM21 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.