TRIM8

Summary

TRIM8 (tripartite motif containing 8, HGNC:15579) is a protein-coding gene on chromosome 10q24.32, encoding E3 ubiquitin-protein ligase TRIM8 (Q9BZR9). E3 ubiquitin-protein ligase that participates in multiple biological processes including cell survival, differentiation, apoptosis, and in particular, the innate immune response.

This gene encodes a member of the tripartite motif (TRIM) protein family. Based on similarities to other proteins, the encoded protein is suspected to be an E3 ubiquitin-protein ligase. Regulation of this gene may be altered in some cancers. Mutations resulting in a truncated protein product have been observed in early-onset epileptic encephalopathy (EOEE).

Source: NCBI Gene 81603 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal segmental glomerulosclerosis and neurodevelopmental syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 21
• Clinical variants (ClinVar): 438 total — 10 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 101
• MANE Select transcript: NM_030912

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15579
Approved symbol	TRIM8
Name	tripartite motif containing 8
Location	10q24.32
Locus type	gene with protein product
Status	Approved
Aliases	GERP
Ensembl gene	ENSG00000171206
Ensembl biotype	protein_coding
OMIM	606125
Entrez	81603

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000302424, ENST00000462202, ENST00000479004, ENST00000487927, ENST00000642304, ENST00000642664, ENST00000643100, ENST00000643376, ENST00000643721, ENST00000644572, ENST00000644914, ENST00000644979, ENST00000645961, ENST00000646349, ENST00000646757, ENST00000710327, ENST00000936883, ENST00000936884

RefSeq mRNA: 2 — MANE Select: NM_030912 NM_001345950, NM_030912

CCDS: CCDS31274

Canonical transcript exons

ENST00000643721 — 6 exons

Exon	Start	End
ENSE00003502671	102654653	102654748
ENSE00003538108	102656270	102656385
ENSE00003651899	102656106	102656137
ENSE00003673324	102655080	102655313
ENSE00003822827	102656747	102658318
ENSE00004011475	102644479	102645187

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1560 / max 108.5483, expressed in 1793 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106746	3.8543	1395
106744	3.8168	1313
106750	1.9626	1133
106742	0.5948	364
106748	0.4385	239
106745	0.2994	156
106751	0.1371	24
106743	0.0443	14
106747	0.0082	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.88	gold quality
nasal cavity epithelium	UBERON:0005384	97.79	gold quality
medial globus pallidus	UBERON:0002477	97.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.56	gold quality
nasal cavity mucosa	UBERON:0001826	97.50	gold quality
globus pallidus	UBERON:0001875	97.33	gold quality
pancreatic ductal cell	CL:0002079	97.18	gold quality
mucosa of stomach	UBERON:0001199	96.98	gold quality
renal medulla	UBERON:0000362	96.92	gold quality
pericardium	UBERON:0002407	96.89	gold quality
right coronary artery	UBERON:0001625	96.83	gold quality
epithelium of nasopharynx	UBERON:0001951	96.68	gold quality
right lung	UBERON:0002167	96.60	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.56	gold quality
mammary duct	UBERON:0001765	96.55	gold quality
amygdala	UBERON:0001876	96.50	gold quality
adipose tissue	UBERON:0001013	96.49	gold quality
tibial nerve	UBERON:0001323	96.49	gold quality
descending thoracic aorta	UBERON:0002345	96.49	gold quality
caudate nucleus	UBERON:0001873	96.45	gold quality
endocervix	UBERON:0000458	96.39	gold quality
nucleus accumbens	UBERON:0001882	96.35	gold quality
putamen	UBERON:0001874	96.31	gold quality
right uterine tube	UBERON:0001302	96.27	gold quality
body of pancreas	UBERON:0001150	96.26	gold quality
metanephros cortex	UBERON:0010533	96.26	gold quality
cortex of kidney	UBERON:0001225	96.24	gold quality
epithelium of mammary gland	UBERON:0003244	96.24	gold quality
connective tissue	UBERON:0002384	96.21	gold quality
pylorus	UBERON:0001166	96.20	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
JUN	Activation

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

82 targeting TRIM8, 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-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621

Literature-anchored findings (GeneRIF, showing 30)

• interacts with SOCS-1 (PMID:12163497)
• Gerp transcribes interferon-gamma in epithelial and lymphoid cells and is expressed almost ubiquitously in tissues. (PMID:15345195)
• Among genes correlated to nodal metastatic progression, we verified in vitro that NM23-H3 reduced cell motility and TRIM8 were a growth suppressor. (PMID:17900511)
• These findings indicate that TRIM8 enhances the STAT3-dependent signal pathway by inhibiting the function of PIAS3. (PMID:20516148)
• TRIM8 modulates translocation of phosphorylated STAT3 into the nucleus through interaction with Hsp90beta and consequently regulates transcription of Nanog in embryonic stem cells. (PMID:21689689)
• Tripartite motif 8 (TRIM8) modulates TNFalpha- and IL-1beta-triggered NF-kappaB activation by targeting TAK1 for K63-linked polyubiquitination. (PMID:22084099)
• TRIM8 is a p53 direct target gene that induces p53 stabilization and promotes the degradation of MDM2 protein. (PMID:22262183)
• Nucleo-cytoplasmic trafficking of TRIM8, a novel oncogene, is involved in positive regulation of TNF induced NF-kappaB pathway. (PMID:23152791)
• These findings provide the first mechanistic link between TRIM8 and the drug resistance of clear cell Renal Cell Carcinoma (PMID:25277184)
• Our study provides evidences that TRIM8 may participate in the carcinogenesis and progression of glioma and that the transcriptional repression of TRIM8 might have potential value for predicting poor prognosis in glioma patients. (PMID:26077989)
• A pathogenic effect of a heterozygous truncating mutation in the tripartite motif containing 8 (TRIM8) gene on the postnatal development of the human brain. (PMID:27346735)
• TRIM8 activates STAT3 by suppressing the expression of PIAS3, an inhibitor of STAT3, most likely through E3-mediated ubiquitination and proteasomal degradation. (PMID:28100038)
• we provided evidence that TRIM8 and its regulators miR-17-5p and miR-106b-5 participate to a feedback loop controlling cell proliferation through the reciprocal modulation of p53, miR-34a and N-MYC. (PMID:28327152)
• In the current study the authors identified TRIM8, RING E3 Ligase, as a novel regulator of autophagy during DNA damage response. (PMID:29678622)
• TRIM8 is a novel gene responsible for epileptic encephalopathy, possibly associated with nephrotic syndrome. (PMID:30244534)
• TRIM8 knockdown effectively protected lipopolysaccharide-induced acute liver failure against inflammation and oxidative stress largely dependent on the promotion of AMPKalpha pathway. (PMID:30527811)
• The findings uncover a previously unknown regulatory mechanism of type I interferon production in Plasmacytoid dendritic cells by which TRIM8 and Pin1 oppositely regulate the stability of interferon regulatory factor 7. (PMID:31799391)
• TRIM8 interacts with KIF11 and KIFC1 and controls bipolar spindle formation and chromosomal stability. (PMID:31904480)
• Knockdown of TRIM8 Attenuates IL-1beta-induced Inflammatory Response in Osteoarthritis Chondrocytes Through the Inactivation of NF-kappaB Pathway. (PMID:32757662)
• Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia. (PMID:32929213)
• Down-regulation of long noncoding RNA LINC00472 alleviates sepsis-induced acute hepatic injury by regulating miR-373-3p/TRIM8 axis. (PMID:33129786)
• De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. (PMID:33508234)
• TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma. (PMID:34329586)
• Circular RNA circ_0002594 regulates PDGF-BB-induced proliferation and migration of human airway smooth muscle cells via sponging miR-139-5p/TRIM8 in asthma. (PMID:35470728)
• Salvianolic acid B inhibits myocardial I/R-induced ROS generation and cell apoptosis by regulating the TRIM8/GPX1 pathway. (PMID:35968584)
• TRIM8: a double-edged sword in glioblastoma with the power to heal or hurt. (PMID:36690946)
• Mutual regulation between TRIM21 and TRIM8 via K48-linked ubiquitination. (PMID:37914816)
• TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4alpha stability. (PMID:38237865)
• Tripartite motif 8 promotes the progression of hepatocellular carcinoma via mediating ubiquitination of HNF1alpha. (PMID:38879600)
• TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation. (PMID:38881325)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	trim8b	ENSDARG00000060729
danio_rerio	trim8a	ENSDARG00000090512
mus_musculus	Trim8	ENSMUSG00000025034
rattus_norvegicus	Trim8	ENSRNOG00000019968

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), TRIM21 (ENSG00000132109), 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)

Protein

Protein identifiers

E3 ubiquitin-protein ligase TRIM8 — Q9BZR9 (reviewed: Q9BZR9)

Alternative names: Glioblastoma-expressed RING finger protein, RING finger protein 27, RING-type E3 ubiquitin transferase TRIM8, Tripartite motif-containing protein 8

All UniProt accessions (9): A0A2R8Y500, A0A2R8Y580, A0A2R8Y5K0, A0A2R8YCF6, A0A2R8YD00, A0A2R8YFP1, A0A2U3TZI0, Q9BZR9, R4GN03

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that participates in multiple biological processes including cell survival, differentiation, apoptosis, and in particular, the innate immune response. Participates in the activation of interferon-gamma signaling by promoting proteasomal degradation of the repressor SOCS1. Plays a positive role in the TNFalpha and IL-1beta signaling pathways. Mechanistically, induces the ‘Lys-63’-linked polyubiquitination of MAP3K7/TAK1 component leading to the activation of NF-kappa-B. Also modulates STAT3 activity through negative regulation of PIAS3, either by degradation of PIAS3 through the ubiquitin-proteasome pathway or exclusion of PIAS3 from the nucleus. Negatively regulates TLR3/4-mediated innate immune response by catalyzing ‘Lys-6’- and ‘Lys-33’-linked polyubiquitination of TICAM1 and thereby disrupting the TICAM1-TBK1 interaction.

Subunit / interactions. Homodimer. Interacts with SOCS1 (via) SH2 domain and SOCS box. Interacts with HSP90AB1; prevents nucleus translocation of phosphorylated STAT3 and HSP90AB1. Interacts with MAP3K7/TAK1. Interacts with PIAS3. Interacts with TICAM1. Interacts with TRIM15; this interaction prevents TRIM8 cytoplasmic translocation.

Subcellular location. Cytoplasm. Nucleus. Nuclear body.

Tissue specificity. Widely expressed. Expressed in glomerular podocytes of kidneys.

Disease relevance. Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS) [MIM:619428] An autosomal dominant disorder characterized by global developmental delay associated with variable features of focal segmental glomerulosclerosis, a renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Some patients have transient proteinuria and others require renal transplant. Neurodevelopmental features are also variable, with some patients having only mildly impaired intellectual development, and others having a severe developmental disorder associated with early-onset refractory seizures or epileptic encephalopathy. Additional features, including feeding difficulties, poor overall growth, and non-specific dysmorphic facial features, are commonly observed. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The coiled coil domain is required for homodimerization. The region immediately C-terminal to the RING motif is sufficient to mediate the interaction with SOCS1.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the TRIM/RBCC family.

RefSeq proteins (2): NP_001332879, NP_112174* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR027370	Znf-RING_euk	Domain
IPR051051	E3_ubiq-ligase_TRIM/RNF	Family
IPR058030	TRIM8/14/16/25/29/45/65_CC	Domain

Pfam: PF13445, PF25600

UniProt features (21 total): sequence variant 10, mutagenesis site 5, zinc finger region 3, chain 1, sequence conflict 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZR9-F1	72.26	0.51

Functional residue map

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

Mutagenesis-validated functional residues (5):

Position	Phenotype
15	complete loss of ubiquitination activity on map3k7/tak1.
15	complete loss of ubiquitination activity on ticam1.
18	complete loss of ubiquitination activity on map3k7/tak1.
18	complete loss of ubiquitination activity on ticam1.
30	complete loss of ubiquitination activity on ticam1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-877300	Interferon gamma signaling

MSigDB gene sets: 492 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, TAATAAT_MIR126, WANG_CLIM2_TARGETS_UP, MYOGENIN_Q6, GCM_PTPRD, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, PEREZ_TP63_TARGETS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, MAZ_Q6, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM

GO Biological Process (13): canonical NF-kappaB signal transduction (GO:0007249), positive regulation of autophagy (GO:0010508), stem cell population maintenance (GO:0019827), negative regulation of viral transcription (GO:0032897), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), suppression of viral release by host (GO:0044790), innate immune response (GO:0045087), host-mediated suppression of symbiont invasion (GO:0046597), protein K63-linked ubiquitination (GO:0070534), positive regulation of protein localization to nucleus (GO:1900182), immune system process (GO:0002376), protein ubiquitination (GO:0016567), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (8): transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), PML body (GO:0016605), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interferon Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
intracellular signaling cassette	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
multicellular organismal process	1
maintenance of cell number	1
viral transcription	1
regulation of viral transcription	1
negative regulation of viral process	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
defense response to virus	1
immune response	1
defense response to symbiont	1
innate immune response	1
host-mediated perturbation of symbiont process	1
protein polyubiquitination	1
protein localization to nucleus	1
regulation of protein localization to nucleus	1
positive regulation of protein localization	1
biological_process	1
protein modification by small protein conjugation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
transition metal ion binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1176 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIM8	SOCS1	O15524	936
TRIM8	TRAT1	Q6PIZ9	794
TRIM8	BBOX1	O75936	688
TRIM8	PIAS3	Q9Y6X2	678
TRIM8	MRTFA	Q969V6	660
TRIM8	TRIM32	Q13049	619
TRIM8	SMAD9	O15198	599
TRIM8	MAF	O75444	576
TRIM8	TRIM66	O15016	575
TRIM8	TRIM23	P36406	544
TRIM8	TRIM24	O15164	495
TRIM8	TRIM40	Q6P9F5	491
TRIM8	TRIM3	O75382	483
TRIM8	SIAH1	Q8IUQ4	467
TRIM8	TRIM14	Q14142	465

IntAct

134 interactions, top by confidence:

A	B	Type	Score
UBE2D1	TRIM8	psi-mi:“MI:0915”(physical association)	0.670
UBE2D4	TRIM8	psi-mi:“MI:0915”(physical association)	0.670
UBE2L6	TRIM8	psi-mi:“MI:0915”(physical association)	0.670
TRIM8	UBE2D4	psi-mi:“MI:0915”(physical association)	0.670
TRIM8	TRIM8	psi-mi:“MI:0915”(physical association)	0.630
MTURN	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
YOD1	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
OTUB2	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
RAD23A	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
LONRF1	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
UBXN7	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
LNX1	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
TNIP3	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
USP5	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
DCUN1D1	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
HOXA1	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
CATSPER1	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
TNS2	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
NUDT10	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
UBASH3A	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
TRIM8	FAM124B	psi-mi:“MI:0915”(physical association)	0.560
TNPO2	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
RNF168	TRIM8	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	TRIM8	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (125): TRIM8 (Synthetic Growth Defect), TRIM8 (Synthetic Growth Defect), TRIM8 (Two-hybrid), TRIM8 (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), TRIM8 (Affinity Capture-Western), TRIM8 (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), TRIM8 (Affinity Capture-MS), TICAM1 (Affinity Capture-Western), TRIM8 (Affinity Capture-Western), TICAM1 (Biochemical Activity), TRIM8 (Affinity Capture-MS), TRIM8 (Two-hybrid), TRIM8 (Two-hybrid)

ESM2 similar proteins: A0JNG4, A1L3T7, B1AVH7, B5DFA1, D2H0G5, E1U8D0, E9QHE3, I1VZH0, O08629, O60826, O75052, O94964, P58660, P86182, P98171, Q13263, Q149G0, Q1LWB0, Q1RMI8, Q3ULW6, Q3V3A7, Q571B6, Q58D79, Q5JV73, Q5R8S0, Q62318, Q6P4K6, Q6PGG2, Q6ZQ29, Q6ZRF8, Q768S4, Q7TSI1, Q80TQ5, Q8BL43, Q8C7B8, Q8IWE5, Q8K1S6, Q8N163, Q8TF30, Q8VDP4

Diamond homologs: A0A3B3IT33, A6NCK2, A6NDI0, A6NGJ6, A6NI03, A6NLI5, B0BLU1, C9J1S8, I1YAP6, O00478, O00481, O15344, O75677, O75678, O75679, O76064, P0CI25, P0CI26, P18892, P19474, P62603, P86448, P86449, Q13410, Q2HJ46, Q3C1V9, Q3TL54, Q4KLN8, Q5EBN2, Q5PQN2, Q5R4I2, Q5R996, Q61510, Q62556, Q6INS5, Q6MFY8, Q6UX41, Q6UXE8, Q6ZWI9, Q7T308

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	TRIM8	ubiquitination
TRIM8	“up-regulates activity”	MAP3K7	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	34.1×	2e-05
Ovarian tumor domain proteases	6	30.9×	5e-06
Negative regulators of DDX58/IFIH1 signaling	5	30.2×	3e-05
E3 ubiquitin ligases ubiquitinate target proteins	5	17.9×	3e-04
Antigen processing: Ubiquitination & Proteasome degradation	19	13.1×	2e-14
Class I MHC mediated antigen processing & presentation	9	11.7×	6e-06
Neddylation	7	6.1×	3e-03
Adaptive Immune System	9	5.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	7	37.0×	7e-08
protein autoubiquitination	10	36.0×	3e-11
protein K63-linked ubiquitination	7	28.8×	4e-07
protein polyubiquitination	12	21.3×	4e-11
ubiquitin-dependent protein catabolic process	14	16.0×	3e-11
protein ubiquitination	25	15.9×	2e-21
protein K48-linked ubiquitination	6	15.6×	1e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	10	8.0×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	5
Uncertain significance	182
Likely benign	192
Benign	16

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1189042	NM_030912.3(TRIM8):c.1338T>A (p.Tyr446Ter)	Pathogenic
1189043	NM_030912.3(TRIM8):c.1331C>A (p.Ser444Ter)	Pathogenic
1189046	NM_030912.3(TRIM8):c.1198_1220del (p.Tyr400fs)	Pathogenic
1344829	NM_030912.3(TRIM8):c.1240C>T (p.Gln414Ter)	Pathogenic
1699050	NM_030912.3(TRIM8):c.1257C>A (p.Cys419Ter)	Pathogenic
1805889	NM_030912.3(TRIM8):c.1357C>T (p.Gln453Ter)	Pathogenic
2582847	NM_030912.3(TRIM8):c.1200C>A (p.Tyr400Ter)	Pathogenic
4073639	NM_030912.3(TRIM8):c.1310C>G (p.Ser437Ter)	Pathogenic
4086441	NM_030912.3(TRIM8):c.1390A>T (p.Lys464Ter)	Pathogenic
986857	NM_030912.3(TRIM8):c.1267C>T (p.Gln423Ter)	Pathogenic
1344830	NM_030912.3(TRIM8):c.1461C>G (p.Tyr487Ter)	Likely pathogenic
1526073	NM_030912.3(TRIM8):c.1200C>G (p.Tyr400Ter)	Likely pathogenic
1703082	NM_030912.3(TRIM8):c.1062del (p.Pro355fs)	Likely pathogenic
2159491	NM_030912.3(TRIM8):c.1120del (p.Ala374fs)	Likely pathogenic
2627921	NM_030912.3(TRIM8):c.1474del (p.His492fs)	Likely pathogenic

SpliceAI

1028 predictions. Top by Δscore:

Variant	Effect	Δscore
10:102654648:TGCA:T	acceptor_loss	1.0000
10:102654649:GCA:G	acceptor_loss	1.0000
10:102654650:CA:C	acceptor_loss	1.0000
10:102654651:A:AG	acceptor_gain	1.0000
10:102654651:AGA:A	acceptor_loss	1.0000
10:102654652:G:GA	acceptor_gain	1.0000
10:102654652:GA:G	acceptor_gain	1.0000
10:102654652:GAA:G	acceptor_gain	1.0000
10:102654652:GAAGA:G	acceptor_gain	1.0000
10:102654746:G:GT	donor_gain	1.0000
10:102654747:AGG:A	donor_loss	1.0000
10:102655069:T:TA	acceptor_gain	1.0000
10:102655072:A:AG	acceptor_gain	1.0000
10:102655072:ACTC:A	acceptor_gain	1.0000
10:102655073:C:G	acceptor_gain	1.0000
10:102655076:GCAG:G	acceptor_loss	1.0000
10:102655077:CAG:C	acceptor_loss	1.0000
10:102655078:A:AC	acceptor_loss	1.0000
10:102655078:A:AG	acceptor_gain	1.0000
10:102655078:AG:A	acceptor_gain	1.0000
10:102655079:G:A	acceptor_loss	1.0000
10:102655079:G:GA	acceptor_gain	1.0000
10:102655079:GG:G	acceptor_gain	1.0000
10:102655079:GGA:G	acceptor_gain	1.0000
10:102655079:GGAGA:G	acceptor_gain	1.0000
10:102655245:G:GT	donor_gain	1.0000
10:102655285:A:G	donor_gain	1.0000
10:102655293:G:GT	donor_gain	1.0000
10:102655296:G:GT	donor_gain	1.0000
10:102655311:A:T	donor_gain	1.0000

AlphaMissense

3608 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:102644655:T:A	L13H	1.000
10:102644655:T:C	L13P	1.000
10:102644660:T:A	C15S	1.000
10:102644660:T:C	C15R	1.000
10:102644661:G:A	C15Y	1.000
10:102644661:G:C	C15S	1.000
10:102644661:G:T	C15F	1.000
10:102644662:C:G	C15W	1.000
10:102644667:T:A	I17N	1.000
10:102644667:T:C	I17T	1.000
10:102644667:T:G	I17S	1.000
10:102644669:T:A	C18S	1.000
10:102644669:T:C	C18R	1.000
10:102644670:G:A	C18Y	1.000
10:102644670:G:C	C18S	1.000
10:102644670:G:T	C18F	1.000
10:102644671:C:G	C18W	1.000
10:102644673:T:C	L19P	1.000
10:102644681:T:A	F22I	1.000
10:102644681:T:C	F22L	1.000
10:102644682:T:C	F22S	1.000
10:102644682:T:G	F22C	1.000
10:102644683:C:A	F22L	1.000
10:102644683:C:G	F22L	1.000
10:102644691:C:A	P25Q	1.000
10:102644700:T:A	L28Q	1.000
10:102644700:T:C	L28P	1.000
10:102644705:T:C	C30R	1.000
10:102644706:G:A	C30Y	1.000
10:102644707:C:G	C30W	1.000

dbSNP variants (sampled 300 via entrez): RS1000204894 (10:102649477 C>A,T), RS1000353444 (10:102643234 G>T), RS1000497655 (10:102654909 G>A), RS1000753162 (10:102642725 G>T), RS1000908048 (10:102643910 G>A), RS1001087730 (10:102653406 G>A,T), RS1001126598 (10:102644084 G>A,C,T), RS1001140014 (10:102653659 T>C), RS1001232015 (10:102655229 C>T), RS1001495595 (10:102655870 G>T), RS1001611595 (10:102655660 T>G), RS1001947836 (10:102644444 G>A), RS1001995789 (10:102657982 C>A,T), RS1002123194 (10:102649776 C>T), RS1002260623 (10:102647006 G>C)

Disease associations

OMIM: gene MIM:606125 | disease phenotypes: MIM:619428

GenCC curated gene-disease

Disease	Classification	Inheritance
focal segmental glomerulosclerosis and neurodevelopmental syndrome	Definitive	Autosomal dominant
genetic developmental and epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
focal segmental glomerulosclerosis and neurodevelopmental syndrome	Definitive	AD

Mondo (3): focal segmental glomerulosclerosis and neurodevelopmental syndrome (MONDO:0100111), focal segmental glomerulosclerosis (MONDO:0100313), genetic developmental and epileptic encephalopathy (MONDO:0100062)

Orphanet (0):

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000070	Ureterocele
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000099	Glomerulonephritis
HP:0000100	Nephrotic syndrome
HP:0000110	Renal dysplasia
HP:0000175	Cleft palate
HP:0000212	Gingival overgrowth
HP:0000252	Microcephaly
HP:0000319	Smooth philtrum
HP:0000340	Sloping forehead
HP:0000343	Long philtrum
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000664	Synophrys
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000752	Hyperactivity
HP:0000817	Reduced eye contact
HP:0000826	Precocious puberty
HP:0000954	Single transverse palmar crease
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001942_1	Prostate cancer	5.000000e-10
GCST002539_4	Schizophrenia	6.000000e-19
GCST003045_28	Ulcerative colitis	3.000000e-07
GCST004521_172	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_53	Autism spectrum disorder or schizophrenia	9.000000e-10
GCST004557_15	Body mass index	2.000000e-07
GCST004558_12	Body mass index (joint analysis main effects and physical activity interaction)	4.000000e-08
GCST004559_10	Body mass index in physically active individuals	4.000000e-06
GCST005956_50	Waist-to-hip ratio adjusted for BMI	8.000000e-06
GCST005958_15	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_36	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-07
GCST006948_28	Feeling nervous	1.000000e-13
GCST007201_158	Schizophrenia	2.000000e-11
GCST007269_190	Pulse pressure	4.000000e-15
GCST007327_188	Smoking status (ever vs never smokers)	6.000000e-12
GCST009600_73	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-09
GCST010002_298	Refractive error	3.000000e-22
GCST010703_271	Brain morphology (MOSTest)	5.000000e-13
GCST012227_618	Hip circumference adjusted for BMI	1.000000e-09
GCST90011900_43	Serum alkaline phosphatase levels	7.000000e-24
GCST90020029_145	Waist circumference adjusted for body mass index	9.000000e-09

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009597	feeling nervous measurement
EFO:0005763	pulse pressure measurement
EFO:0004318	smoking behavior
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	7
methylmercuric chloride	increases expression, affects cotreatment	3
(+)-JQ1 compound	affects expression, increases reaction, decreases expression	3
bisphenol A	increases expression, increases methylation	2
trichostatin A	affects expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
dimethylselenide	increases expression, increases oxidation	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one	decreases expression, increases activity	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Decitabine	increases expression	1
Vorinostat	decreases expression	1
Panobinostat	affects expression, increases reaction	1
Acetaminophen	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TU59	HAP1 TRIM8 (-) 1	Cancer cell line	Male
CVCL_TU60	HAP1 TRIM8 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT01164098	PHASE3	TERMINATED	Rituximab to Prevent Recurrence of Proteinuria
NCT02683889	PHASE3	COMPLETED	Use of Acthar in Patients With FSGS That Will be Undergoing Renal Transplantation
NCT03298698	PHASE3	UNKNOWN	Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
NCT03493685	PHASE3	COMPLETED	Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS)
NCT05183646	PHASE3	RECRUITING	A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB
NCT07220083	PHASE3	RECRUITING	A Study to Find Out if BI 764198 Helps Adults and Adolescents With a Kidney Condition Called Focal Segmental Glomerulosclerosis (FSGS)
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT00550342	PHASE2	WITHDRAWN	Rituximab Treatment of Focal Segmental Glomerulosclerosis
NCT00814255	PHASE2	COMPLETED	Novel Therapies for Resistant FSGS (FONTII): Phase II Clinical Trial
NCT01613118	PHASE2	COMPLETED	Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT03366337	PHASE2	COMPLETED	A Phase 2 Trial of the Safety and Efficacy of Bardoxolone Methyl in Patients With Rare Chronic Kidney Diseases - PHOENIX
NCT03448692	PHASE2	TERMINATED	A Study to Evaluate PF-06730512 in Adults With Focal Segmental Glomerulosclerosis (FSGS)
NCT03536754	PHASE2	COMPLETED	A Study of CCX140-B in Subjects With FSGS
NCT03598036	PHASE2	TERMINATED	Dose-Exploration Evaluating the Efficacy and Safety of Voclosporin in Subjects With Focal Segmental Glomerulosclerosis
NCT03649152	PHASE2	COMPLETED	Safety and Effectiveness of Propagermanium in Focal Segmental Glomerulosclerosis Participants Receiving Irbesartan
NCT03703908	PHASE2	TERMINATED	A Study of CCX140-B in Subjects With Primary FSGS and Nephrotic Syndrome
NCT04009668	PHASE2	COMPLETED	Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease
NCT04573920	PHASE2	ACTIVE_NOT_RECRUITING	Atrasentan in Patients With Proteinuric Glomerular Diseases
NCT05003986	PHASE2	RECRUITING	Study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases
NCT05267262	PHASE2	COMPLETED	Study to Evaluate R3R01 in Patients With Alport Syndrome and Patients With Focal Segmental Glomerulosclerosis
NCT05441826	PHASE2	TERMINATED	Efficacy and Safety of VB119 in Subjects With Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS)
NCT06500702	PHASE2	RECRUITING	A Study to Evaluate the Efficacy and Safety of Frexalimab, Brivekimig, or Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis or Minimal Change Disease
NCT06664814	PHASE2	RECRUITING	An Open-Label Phase 2 Study of N-Acetyl-D-Mannosamine (ManNAc) in Subjects With Primary Focal Segmental Glomerulosclerosis
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases
NCT07268638	PHASE2	RECRUITING	A Study of Praliciguat in Participants With Focal Segmental Glomerulosclerosis (FSGS)
NCT07614477	PHASE2	RECRUITING	Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of EVER001 in Participants With Selected Proteinuric Glomerular Diseases
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT00464321	PHASE1	COMPLETED	Safety Study of GC1008 in Patients With Focal Segmental Glomerulosclerosis (FSGS) of Single Doses of GC1008 in Patients With Treatment Resistant Idiopathic FSGS
NCT00782561	PHASE1	TERMINATED	Safety and Pharmacokinetics of FG-3019 in Adolescents and Adults With Focal Segmental Glomerulosclerosis (FSGS)
NCT00816478	PHASE1	TERMINATED	Effect of Oral Galactose on Focal Segmental Glomerulosclerosis (FSGS) Permeability Factor
NCT00816504	PHASE1	WITHDRAWN	Effect of Galactose on Permeblity Factor in Patients With FSGS and CKD Stage 5
NCT02382874	PHASE1	UNKNOWN	Allogenic AD-MSC Transplantation in Idiopathic Nephrotic Syndrome (Focal Segmental Glomerulosclerosis)