TRIM65

Summary

TRIM65 (tripartite motif containing 65, HGNC:27316) is a protein-coding gene on chromosome 17q25.1, encoding E3 ubiquitin-protein ligase TRIM65 (Q6PJ69). E3 ubiquitin ligase that plays a role in several processes including innate immnity, autophagy or inflammation.

Enables ubiquitin protein ligase activity. Involved in negative regulation of inflammatory response; positive regulation of metabolic process; and protein polyubiquitination. Located in cytosol and nucleoplasm. Is active in cytoplasm.

Source: NCBI Gene 201292 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 121 total
• MANE Select transcript: NM_173547

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27316
Approved symbol	TRIM65
Name	tripartite motif containing 65
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141569
Ensembl biotype	protein_coding
OMIM	619408
Entrez	201292

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000269383, ENST00000540128, ENST00000540812, ENST00000543309, ENST00000591668, ENST00000592642, ENST00000648382, ENST00000909232, ENST00000924710, ENST00000924711, ENST00000924712, ENST00000946120, ENST00000946121, ENST00000946122

RefSeq mRNA: 2 — MANE Select: NM_173547 NM_001256124, NM_173547

CCDS: CCDS11732

Canonical transcript exons

ENST00000269383 — 6 exons

Exon	Start	End
ENSE00000949825	75892011	75892185
ENSE00000949828	75891813	75891878
ENSE00001195870	75892267	75892500
ENSE00001195875	75892755	75892850
ENSE00001195877	75896524	75896951
ENSE00001223068	75888963	75891347

Expression profiles

Bgee: expression breadth ubiquitous, 171 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2801 / max 82.5033, expressed in 1743 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168136	7.6887	1724
168135	0.5914	291

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.60	gold quality
oviduct epithelium	UBERON:0004804	96.87	gold quality
tendon of biceps brachii	UBERON:0008188	96.77	silver quality
ileal mucosa	UBERON:0000331	91.36	gold quality
granulocyte	CL:0000094	88.16	gold quality
cerebellar hemisphere	UBERON:0002245	88.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.89	gold quality
cerebellar cortex	UBERON:0002129	87.78	gold quality
endocervix	UBERON:0000458	86.84	gold quality
body of uterus	UBERON:0009853	86.65	gold quality
right coronary artery	UBERON:0001625	86.55	gold quality
ectocervix	UBERON:0012249	86.39	gold quality
right ovary	UBERON:0002118	86.34	gold quality
tibialis anterior	UBERON:0001385	86.24	silver quality
cerebellum	UBERON:0002037	85.77	gold quality
apex of heart	UBERON:0002098	85.61	gold quality
left ovary	UBERON:0002119	85.27	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.27	gold quality
right lobe of thyroid gland	UBERON:0001119	85.24	gold quality
left uterine tube	UBERON:0001303	85.11	gold quality
body of pancreas	UBERON:0001150	85.03	gold quality
lower esophagus	UBERON:0013473	84.76	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.75	gold quality
vagina	UBERON:0000996	84.51	gold quality
gastrocnemius	UBERON:0001388	84.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.38	gold quality
muscle of leg	UBERON:0001383	84.35	gold quality
lower esophagus mucosa	UBERON:0035834	84.23	gold quality
tibial nerve	UBERON:0001323	84.14	gold quality
tendon	UBERON:0000043	84.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting TRIM65, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104

Literature-anchored findings (GeneRIF, showing 24)

• TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6. (PMID:24778252)
• TRIM65 is a potential oncogenic protein, highly likely through p53 inactivation (PMID:27012201)
• These results suggest that rs3744028 in TRIM65 is not associated with leukoaraiosis (LA) risk in the Chinese population. However, the association of rs3744028 (TRIM65) with LA before Bonferroni correction and Sidak correction is worth highlighting. (PMID:27583843)
• SopA-mediated ubiquitination inhibits and triggers the proteasomal degradation of TRIM56 and TRIM65 during Salmonella infection. (PMID:28084320)
• ARRDC4 interacted with MDA5 via the arrestin-like N domain, and further recruited TRIM65 to enhance the K63 ubiquitination of MDA5 (PMID:28594402)
• TRIM65 exerted oncogenic activities via ubiquitylation of Axin1 to activate the beta-catenin signaling pathway. (PMID:28754688)
• TRIM65 silencing inhibited cell proliferation, promoted cell apoptosis and arrested cell cycle, highly like through blocking ERK1/2 pathway. (PMID:30039885)
• Results suggest that the overexpression of tripartite motif-containing protein 65 (TRIM65) has an essential oncogenic role via ubiquitination of annexin A2 (ANXA2) in urothelial carcinoma of the bladder (UCB) pathogenesis, and that could be used as a prognostic marker and/or therapeutic target for UCB. (PMID:30075204)
• TRIM65 binds to the N-terminus of p53 tumor suppressor and thus competes with MDM2 for p53 binding. (PMID:30454706)
• this study first demonstrated that a novel LINC01857/miR-1281/TRIM65 signaling regulates glioma progression (PMID:31049960)
• TRIM65 knockdown attenuates autophagy and cisplatin resistance in A549/DDP cells via regulating miR-138-5p. (PMID:31160576)
• TRIM65 mediates ubiquitination of ARHGAP35, whose degradation leads to elevated Rho GTPase activity and colorectal cancer metastasis. (PMID:31332286)
• TRIM65 Promotes Invasion of Endometrial Stromal Cells by Activating ERK1/2/C-myc Signaling via Ubiquitination of DUSP6. (PMID:33146694)
• Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases. (PMID:33373584)
• TRIM65 in White Matter Lesions, Innate Immunity, and Tumor. (PMID:33538683)
• LncRNA LINC00963 promotes colorectal cancer cell proliferation and metastasis by regulating miR1281 and TRIM65. (PMID:34498706)
• TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT. (PMID:35218667)
• Knockdown of TRIM65 suppressed the proliferation and invasiveness of gastric cancer cells by restricting the ubiquitin degradation of PPM1A. (PMID:35421368)
• TRIM65 Promotes Malignant Cell Behaviors in Triple-Negative Breast Cancer by Impairing the Stability of LATS1 Protein. (PMID:36035221)
• TRIM65 Suppresses oxLDL-induced Endothelial Inflammation by Interaction with VCAM-1 in Atherogenesis. (PMID:37608612)
• TRIM65 knockout inhibits the development of HCC by polarization tumor-associated macrophages towards M1 phenotype via JAK1/STAT1 signaling pathway. (PMID:38218012)
• TRIM65 promotes vascular smooth muscle cell phenotypic transformation by activating PI3K/Akt/mTOR signaling during atherogenesis. (PMID:38301602)
• Tripartite Motif-Containing Protein 65 (TRIM65) Inhibits Hepatitis B Virus Transcription. (PMID:38932182)
• TRIM65/NF2/YAP1 Signaling Coordinately Orchestrates Metabolic and Immune Advantages in Hepatocellular Carcinoma. (PMID:39005234)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Trim65	ENSMUSG00000054517
rattus_norvegicus	Trim65	ENSRNOG00000024145

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), 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 TRIM65 — Q6PJ69 (reviewed: Q6PJ69)

Alternative names: Tripartite motif-containing protein 65

All UniProt accessions (5): Q6PJ69, H0YG27, H0YGS7, K7EJ59, K7EM44

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase that plays a role in several processes including innate immnity, autophagy or inflammation. Negatively regulates miRNAs by modulating the ubiquitination and stability of TNRC6A, a protein involved in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs. This ubiquitination results in the suppressed expression of miR-138-5p leading to increased autophagy. Upon enteroviral infection, promotes ‘Lys-63’-mediated ubiquitination activation of IFIH1/MDA5 leading to innate signaling cascade. Mechanistically, selectively recognizes MDA5 filaments that occur on dsRNAs. Plays also a role in limitation of inflammation through different mechanisms. First, promotes ‘Lys-48’-mediated ubiquitination of VCAM1 leading to its degradation and limitation of LPS-induced lung inflammation. In addition, negatively regulates inflammasome activation by promoting ’lys48’-linked ubiquitination of NLRP3 which is critical for the inhibition of NLRP3 inflammasome activation in resting macrophages.

Subunit / interactions. Homo-multimerizes. Interacts with ARRDC4.

Subcellular location. Cytoplasm.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the TRIM/RBCC family.

RefSeq proteins (2): NP_001243053, NP_775818* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000315	Znf_B-box	Domain
IPR001841	Znf_RING	Domain
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	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
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR048222	TRIM65_SPRY_PRY	Domain
IPR051051	E3_ubiq-ligase_TRIM/RNF	Family
IPR058030	TRIM8/14/16/25/29/45/65_CC	Domain

Pfam: PF00097, PF00622, PF00643, PF25600

UniProt features (36 total): strand 13, binding site 4, sequence variant 4, turn 3, modified residue 2, helix 2, zinc finger region 2, initiator methionine 1, chain 1, cross-link 1, domain 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7JL4	X-RAY DIFFRACTION	1.92
7JL0	ELECTRON MICROSCOPY	4.3
7JL2	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PJ69-F1	84.99	0.56

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): 125; 95; 98; 117

Post-translational modifications (3): 2, 185, 206

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 138 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_INTERFERON_BETA_PRODUCTION

GO Biological Process (16): positive regulation of autophagy (GO:0010508), positive regulation of protein oligomerization (GO:0032461), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), negative regulation of inflammatory response (GO:0050728), type I interferon-mediated signaling pathway (GO:0060337), protein K63-linked ubiquitination (GO:0070534), protein K48-linked ubiquitination (GO:0070936), antiviral innate immune response (GO:0140374), negative regulation of NLRP3 inflammasome complex assembly (GO:1900226), immune system process (GO:0002376), inflammatory response (GO:0006954), protein ubiquitination (GO:0016567), NLRP3 inflammasome complex assembly (GO:0044546), innate immune response (GO:0045087), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), protein domain specific binding (GO:0019904), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of protein-containing complex assembly	2
positive regulation of type I interferon production	2
protein polyubiquitination	2
NLRP3 inflammasome complex assembly	2
regulation of NLRP3 inflammasome complex assembly	2
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
regulation of protein oligomerization	1
protein complex oligomerization	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
innate immune response	1
defense response to virus	1
negative regulation of protein-containing complex assembly	1
negative regulation of inflammasome-mediated signaling pathway	1
biological_process	1
defense response	1
protein modification by small protein conjugation	1
canonical inflammasome complex assembly	1
immune response	1
defense response to symbiont	1
positive regulation of inflammasome-mediated signaling pathway	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIM65	MRPL38	Q96DV4	612
TRIM65	TRAT1	Q6PIZ9	596
TRIM65	ARRDC4	Q8NCT1	585
TRIM65	TRIM40	Q6P9F5	571
TRIM65	FBF1	Q8TES7	554
TRIM65	WBP2	Q969T9	528
TRIM65	TRIM23	P36406	503
TRIM65	TRIM32	Q13049	502
TRIM65	IFIH1	Q9BYX4	478
TRIM65	A0A087WT04	A0A087WT04	475
TRIM65	TRIM37	O94972	446
TRIM65	BBOX1	O75936	446
TRIM65	NBEAL1	Q6ZS30	437
TRIM65	ECSIT	Q9BQ95	429
TRIM65	PRY	O14603	420

IntAct

54 interactions, top by confidence:

A	B	Type	Score
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
CCNJL	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
C19orf25	TDP2	psi-mi:“MI:0914”(association)	0.530
TRIM65	SRPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
TRIM65	RHOA	psi-mi:“MI:0915”(physical association)	0.400
UBE2U	TRIM65	psi-mi:“MI:0915”(physical association)	0.370
UBE2Z	TRIM65	psi-mi:“MI:0915”(physical association)	0.370
TRIM65	RBCK1	psi-mi:“MI:0915”(physical association)	0.370
ANAPC11	TRIM65	psi-mi:“MI:0915”(physical association)	0.370
TRIM65	MARCHF7	psi-mi:“MI:0915”(physical association)	0.370
TRIM65	MKRN3	psi-mi:“MI:0915”(physical association)	0.370
UBE3A	TRIM65	psi-mi:“MI:0915”(physical association)	0.370
BVLF1	VWA8	psi-mi:“MI:0914”(association)	0.350
P4HA2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
SNX21	POLR1G	psi-mi:“MI:0914”(association)	0.350
CRYL1	MYO9A	psi-mi:“MI:0914”(association)	0.350
GATD1		psi-mi:“MI:0914”(association)	0.350
DOCK5	DPYSL4	psi-mi:“MI:0914”(association)	0.350
PPP4R1L	IFT56	psi-mi:“MI:0914”(association)	0.350
ANKRD39	UBA6	psi-mi:“MI:0914”(association)	0.350
ARHGAP25	UBA6	psi-mi:“MI:0914”(association)	0.350
C19orf25	NBAS	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
INSC	A2ML1	psi-mi:“MI:0914”(association)	0.350
GATD1	MYO9A	psi-mi:“MI:0914”(association)	0.350

BioGRID (102): TRIM65 (Two-hybrid), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-Western), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), TRIM65 (Affinity Capture-MS), AXIN1 (Affinity Capture-Western), ARRDC4 (Affinity Capture-Western)

ESM2 similar proteins: A0JPQ4, E1BD59, O15197, P0C0K6, P62603, Q14142, Q1XH17, Q1XH18, Q3UWZ0, Q5BK82, Q5JZY3, Q5M929, Q5NCC3, Q5RBG2, Q5RKG6, Q5TM55, Q5W0U4, Q640S6, Q6P6S3, Q6PGR9, Q6PJ69, Q6ZMU5, Q7TPM3, Q7YR32, Q80VI1, Q80X56, Q80YW5, Q810I1, Q810I2, Q865W2, Q86UV6, Q86UV7, Q86XT4, Q8BFW4, Q8BVW3, Q8BYG9, Q8C006, Q8C0E3, Q8IUD6, Q8K243

Diamond homologs: A0A0R4I9Y1, A0A0R4IBK5, E9Q555, Q2TBT8, Q63HN8, Q66JE4, Q6NZ21, Q6PJ69, Q8R151, Q96LD4, Q9P2E3, A5WW08, O75382, P29128, P29836, Q54BF0, Q5FWP4, Q5RBG2, Q5RF77, Q5RKG6, Q6P256, Q810L3, Q8C006, Q96EP1, Q9UPQ4, A0JN74, A4QPC6, A6NGJ6, A6NI03, A6NK02, A6NLI5, A6NLU0, B1H278, C9J1S8, F4I443, F8VTS6, O00478, O00481, O15344, O15553

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	TRIM65	ubiquitination
TRIM65	“down-regulates quantity by destabilization”	TNRC6A	polyubiquitination
UBE2D1	“up-regulates activity”	TRIM65	ubiquitination
TRIM65	“down-regulates quantity by destabilization”	ARHGAP35	polyubiquitination
TRIM65	“up-regulates activity”	IFIH1	ubiquitination
TRIM65	“down-regulates activity”	NLRP3	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	104
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1066 predictions. Top by Δscore:

Variant	Effect	Δscore
17:75891344:TAAT:T	acceptor_gain	1.0000
17:75891347:TCTGT:T	acceptor_loss	1.0000
17:75891348:C:CG	acceptor_loss	1.0000
17:75892749:TCGTA:T	donor_loss	1.0000
17:75892750:CGTA:C	donor_loss	1.0000
17:75892751:GTAC:G	donor_loss	1.0000
17:75892752:TA:T	donor_loss	1.0000
17:75892754:C:CT	donor_loss	1.0000
17:75892865:C:CT	acceptor_gain	1.0000
17:75892867:C:CT	acceptor_gain	1.0000
17:75892868:G:T	acceptor_gain	1.0000
17:75892876:C:CT	acceptor_gain	1.0000
17:75892877:A:T	acceptor_gain	1.0000
17:75891345:AAT:A	acceptor_gain	0.9900
17:75891346:AT:A	acceptor_gain	0.9900
17:75891348:C:CC	acceptor_gain	0.9900
17:75891811:A:AC	donor_gain	0.9900
17:75891812:C:CC	donor_gain	0.9900
17:75891812:CT:C	donor_gain	0.9900
17:75892005:TCTTA:T	donor_loss	0.9900
17:75892006:CTTA:C	donor_loss	0.9900
17:75892007:TTACC:T	donor_loss	0.9900
17:75892009:A:AC	donor_gain	0.9900
17:75892009:A:G	donor_loss	0.9900
17:75892009:AC:A	donor_gain	0.9900
17:75892010:C:CC	donor_gain	0.9900
17:75892010:C:CG	donor_loss	0.9900
17:75892010:CC:C	donor_gain	0.9900
17:75892010:CCCA:C	donor_gain	0.9900
17:75892248:ATGC:A	donor_gain	0.9900

AlphaMissense

3319 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:75896845:G:C	F31L	0.985
17:75896845:G:T	F31L	0.985
17:75896847:A:G	F31L	0.985
17:75891229:A:C	F368L	0.984
17:75891229:A:T	F368L	0.984
17:75891231:A:G	F368L	0.984
17:75891064:C:A	W423C	0.980
17:75891064:C:G	W423C	0.980
17:75891175:C:A	W386C	0.978
17:75891175:C:G	W386C	0.978
17:75891177:A:G	W386R	0.978
17:75891177:A:T	W386R	0.978
17:75896623:G:C	F105L	0.978
17:75896623:G:T	F105L	0.978
17:75896625:A:G	F105L	0.978
17:75891222:A:G	W371R	0.977
17:75891222:A:T	W371R	0.977
17:75891066:A:G	W423R	0.975
17:75891066:A:T	W423R	0.975
17:75890902:G:C	F477L	0.973
17:75890902:G:T	F477L	0.973
17:75890904:A:G	F477L	0.973
17:75890941:G:C	F464L	0.971
17:75890941:G:T	F464L	0.971
17:75890943:A:G	F464L	0.971
17:75896848:G:C	N30K	0.970
17:75896848:G:T	N30K	0.970
17:75891083:C:T	G417D	0.969
17:75891208:A:C	C375W	0.967
17:75890866:G:C	F489L	0.964

dbSNP variants (sampled 300 via entrez): RS1000162227 (17:75898241 C>T), RS1000178036 (17:75894148 C>A), RS1000236073 (17:75898003 T>C), RS1000545846 (17:75880013 C>CAAA), RS1000574119 (17:75896818 C>T), RS1000649482 (17:75879583 TGTTAA>T), RS1001175527 (17:75887018 G>A), RS1001455394 (17:75897709 T>A,G), RS1001479959 (17:75897423 A>G), RS1001737006 (17:75896410 G>A), RS1001862037 (17:75891648 G>A), RS1002098492 (17:75879476 G>A), RS1002152471 (17:75879266 A>G), RS1002652048 (17:75879835 C>T), RS1002692893 (17:75879496 G>C)

Disease associations

OMIM: gene MIM:619408 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001109_2	White matter hyperintensity burden	4.000000e-15
GCST003013_1	White matter hyperintensity burden	5.000000e-19
GCST003013_15	White matter hyperintensity burden	3.000000e-19
GCST004346_59	Psoriasis	1.000000e-08
GCST007305_2	White matter hyperintensity volume	1.000000e-11
GCST008129_30	Body mass index	1.000000e-09
GCST010101_18	White matter hyperintensities	5.000000e-36
GCST010727_40	Deep white matter hyperintensities	4.000000e-28
GCST011946_26	White matter hyperintensity volume	2.000000e-42
GCST011947_39	White matter hyperintensity volume	3.000000e-46
GCST011949_43	White matter hyperintensity volume (adjusted for hypertension)	3.000000e-43
GCST011952_1	White matter hyperintensity volume x hypertension interaction (2df)	2.000000e-41
GCST012580_1	White matter hyperintensities	7.000000e-11
GCST90002405_389	Reticulocyte count	1.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005665	white matter hyperintensity measurement
EFO:0004340	body mass index
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	increases methylation, affects expression, decreases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol A	affects expression	1
sodium arsenate	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Bortezomib	decreases expression	1
Leflunomide	decreases expression	1
Arsenic	affects methylation	1
Cisplatin	increases expression, affects cotreatment	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Lactic Acid	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TU46	HAP1 TRIM65 (-) 1	Cancer cell line	Male
CVCL_TU47	HAP1 TRIM65 (-) 2	Cancer cell line	Male
CVCL_TU48	HAP1 TRIM65 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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