TRIM40

Summary

TRIM40 (tripartite motif containing 40, HGNC:18736) is a protein-coding gene on chromosome 6p22.1, encoding E3 ubiquitin ligase TRIM40 (Q6P9F5). E3 ubiquitin-protein ligase that plays a role in the limitation of the innate immune response.

This gene encodes a member of the tripartite motif (TRIM) protein family. The encoded protein may play a role as a negative regulator against inflammation and carcinogenesis in the gastrointestinal tract. Alternatively spliced transcript variants that encode different protein isoforms have been described.

Source: NCBI Gene 135644 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_001286633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18736
Approved symbol	TRIM40
Name	tripartite motif containing 40
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Aliases	RNF35
Ensembl gene	ENSG00000204614
Ensembl biotype	protein_coding
OMIM	616976
Entrez	135644

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000307859, ENST00000376724, ENST00000396581, ENST00000489892, ENST00000883266

RefSeq mRNA: 2 — MANE Select: NM_001286633 NM_001286633, NM_138700

CCDS: CCDS4675, CCDS69069

Canonical transcript exons

ENST00000383610 — 0 exons

Expression profiles

Bgee: expression breadth broad, 41 present calls, max score 84.01.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0495 / max 40.2060, expressed in 8 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66703	0.0398	8
203936	0.0054	2
203935	0.0044	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
duodenum	UBERON:0002114	84.01	gold quality
mucosa of transverse colon	UBERON:0004991	75.58	gold quality
rectum	UBERON:0001052	70.33	gold quality
placenta	UBERON:0001987	67.33	gold quality
vermiform appendix	UBERON:0001154	67.00	gold quality
monocyte	CL:0000576	65.15	gold quality
leukocyte	CL:0000738	64.64	gold quality
small intestine	UBERON:0002108	63.04	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.68	gold quality
small intestine Peyer’s patch	UBERON:0003454	60.95	gold quality
transverse colon	UBERON:0001157	59.78	gold quality
smooth muscle tissue	UBERON:0001135	54.14	gold quality
intestine	UBERON:0000160	52.13	gold quality
bone marrow cell	CL:0002092	50.60	silver quality
colonic epithelium	UBERON:0000397	48.70	silver quality
left testis	UBERON:0004533	48.50	gold quality
testis	UBERON:0000473	48.11	gold quality
colon	UBERON:0001155	47.78	gold quality
adult mammalian kidney	UBERON:0000082	46.00	gold quality
granulocyte	CL:0000094	45.68	silver quality
right testis	UBERON:0004534	45.40	gold quality
blood	UBERON:0000178	45.09	gold quality
kidney	UBERON:0002113	42.20	gold quality
bone marrow	UBERON:0002371	41.72	gold quality
muscle tissue	UBERON:0002385	41.48	gold quality
stromal cell of endometrium	CL:0002255	40.13	gold quality
gall bladder	UBERON:0002110	39.64	silver quality
liver	UBERON:0002107	38.34	gold quality
islet of Langerhans	UBERON:0000006	37.06	gold quality
skeletal muscle tissue	UBERON:0001134	36.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting TRIM40, 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-8485	100.00	77.57	4731
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-1294	98.91	69.26	1030
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-4640-5P	97.42	66.33	1543

Literature-anchored findings (GeneRIF, showing 4)

• findings suggest that TRIM40 inhibits NF-kappaB activity via neddylation of inhibitor of nuclear factor kappaB kinase subunit gamma and that TRIM40 prevents inflammation-associated carcinogenesis in the gastrointestinal tract (PMID:21474709)
• TRIM40 inhibits IgA1-induced proliferation of glomerular mesangial cells by inactivating NLRP3 inflammasome through ubiquitination. (PMID:34763147)
• TRIM40 is a pathogenic driver of inflammatory bowel disease subverting intestinal barrier integrity. (PMID:36755029)
• TRIM40 interacts with ROCK1 directly and inhibits colorectal cancer cell proliferation through the c-Myc/p21 axis. (PMID:39357549)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Trim40	ENSMUSG00000073399
rattus_norvegicus	Trim40	ENSRNOG00000000783

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 ligase TRIM40 — Q6P9F5 (reviewed: Q6P9F5)

Alternative names: Probable E3 NEDD8-protein ligase, RING finger protein 35

All UniProt accessions (2): A0A1U9X8U1, Q6P9F5

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that plays a role in the limitation of the innate immune response. Mediates inhibition of the RLR signaling pathway by ubiquitinating RIGI and IFIH1 receptors, leading to their proteasomal degradation. Also promotes the neddylation of IKBKG/NEMO, stabilizing NFKBIA, and thereby inhibiting of NF-kappa-B nuclear translocation and activation.

Subunit / interactions. Interacts with NEDD8.

Tissue specificity. Highly expressed in normal gastrointestinal epithelia but that is down-regulated in gastrointestinal carcinomas and chronic inflammatory lesions of the gastrointestinal tract.

Similarity. Belongs to the TRIM/RBCC family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6P9F5-1	1	yes
Q6P9F5-2	2

RefSeq proteins (2): NP_001273562, NP_619645 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000315	Znf_B-box	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR050143	TRIM/RBCC	Family

Pfam: PF00097

UniProt features (12 total): binding site 4, sequence variant 3, zinc finger region 2, chain 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P9F5-F1	76.39	0.30

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): 71; 74; 93; 99

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 73 (showing top): GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_PROTEIN_NEDDYLATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_NF_KAPPAB_TRANSCRIPTION_FACTOR_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_REGULATION_OF_NON_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_NON_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (7): negative regulation of cell growth (GO:0030308), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), negative regulation of protein catabolic process (GO:0042177), innate immune response (GO:0045087), protein neddylation (GO:0045116), negative regulation of protein localization to nucleus (GO:1900181), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): cytoplasm (GO:0005737), IkappaB kinase complex (GO:0008385)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
immune response	1
defense response to symbiont	1
protein modification by small protein conjugation	1
protein localization to nucleus	1
regulation of protein localization to nucleus	1
negative regulation of protein localization	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytosol	1
serine/threonine protein kinase complex	1

Protein interactions and networks

STRING

724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIM40	NEDD8	Q15843	918
TRIM40	RIGI	O95786	803
TRIM40	IFIH1	Q9BYX4	785
TRIM40	RNF122	Q9H9V4	593
TRIM40	TRIM65	Q6PJ69	571
TRIM40	TRAT1	Q6PIZ9	570
TRIM40	ZSCAN23	Q3MJ62	535
TRIM40	TRIM29	Q14134	524
TRIM40	RNF125	Q96EQ8	520
TRIM40	TRIM25	Q14258	503
TRIM40	TRIM8	Q9BZR9	491
TRIM40	TRIM56	Q9BRZ2	477
TRIM40	TRIM23	P36406	474
TRIM40	VARS2	Q5ST30	470
TRIM40	RNF135	Q8IUD6	450

IntAct

1 interactions, top by confidence:

BioGRID (104): IFIH1 (Affinity Capture-Western), DDX58 (Affinity Capture-Western), MAVS (Affinity Capture-Western), TRIM40 (Affinity Capture-Western), IFIH1 (Biochemical Activity), DDX58 (Biochemical Activity), TRIM40 (Affinity Capture-MS), TRIM40 (Affinity Capture-Western), NLRP3 (Affinity Capture-Western), PHB2 (Cross-Linking-MS (XL-MS)), DAB1 (Affinity Capture-Western), TRIM40 (Affinity Capture-Western), TRIM40 (Affinity Capture-Western), NBAS (Affinity Capture-MS), ANXA2P2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPQ4, B1WC39, D3Z8N2, E1BD59, G3MY25, O15553, O77666, P59044, P62603, Q12899, Q14142, Q1XH17, Q1XH18, Q1XHT8, Q3UWA4, Q499M4, Q53EQ6, Q5NCC3, Q5RBG2, Q5RKG6, Q5TA31, Q5TM52, Q5TM55, Q6MFY8, Q6P9F5, Q6ZMU5, Q7YR31, Q7YR33, Q7YR34, Q86XR2, Q8BFX1, Q8BVW3, Q8C006, Q8C0E3, Q8NG06, Q8WV44, Q8WZA9, Q920M2, Q923T7, Q96IU2

Diamond homologs: A0A3B3IT33, A0JN74, A2XK56, A4QPC6, A6NCK2, A6NDI0, A6NGJ6, A6NI03, A6NLI5, A6NLU0, B1H278, B8B5U8, C9J1S8, D3YY23, D3Z8N2, F8VTS6, I1YAP6, O00478, O00481, O13033, O54952, O60106, O76064, P0CI25, P0CI26, P18892, P19474, P38398, P48754, P82456, P86448, P86449, Q14258, Q14527, Q1XHT8, Q28DS3, Q2HJ46, Q3C1V9, Q3TL54, Q4KLN8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	TRIM40	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

537 predictions. Top by Δscore:

Variant	Effect	Δscore
6:30145991:TAGG:T	acceptor_loss	1.0000
6:30145992:A:AG	acceptor_gain	1.0000
6:30145992:AG:A	acceptor_gain	1.0000
6:30145993:G:GA	acceptor_gain	1.0000
6:30145993:GG:G	acceptor_gain	1.0000
6:30145993:GGA:G	acceptor_gain	1.0000
6:30145993:GGAAC:G	acceptor_gain	1.0000
6:30146089:GGTG:G	donor_loss	1.0000
6:30146090:G:GA	donor_loss	1.0000
6:30137377:ACAAG:A	donor_loss	0.9900
6:30137379:AAGG:A	donor_loss	0.9900
6:30137382:GT:G	donor_loss	0.9900
6:30145993:GGAA:G	acceptor_gain	0.9900
6:30146091:T:G	donor_loss	0.9900
6:30137223:G:GT	donor_gain	0.9800
6:30146086:GCAG:G	donor_gain	0.9800
6:30146090:G:GG	donor_gain	0.9800
6:30147518:A:AG	acceptor_gain	0.9800
6:30147519:G:GG	acceptor_gain	0.9800
6:30145983:T:TA	acceptor_gain	0.9700
6:30137382:G:GG	donor_gain	0.9600
6:30147519:GA:G	acceptor_gain	0.9600
6:30147514:TCCTA:T	acceptor_loss	0.9500
6:30147515:CCTAG:C	acceptor_loss	0.9500
6:30147516:CTAG:C	acceptor_loss	0.9500
6:30147517:TA:T	acceptor_loss	0.9500
6:30147518:AG:A	acceptor_loss	0.9500
6:30147519:GAAT:G	acceptor_gain	0.9400
6:30145590:T:TA	donor_gain	0.9300
6:30145591:A:AA	donor_gain	0.9300

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000868084 (6:30137811 T>G), RS1001100035 (6:30146202 G>A,T), RS1001492369 (6:30139993 G>A), RS1001725678 (6:30145868 C>A), RS1001762476 (6:30134433 G>A), RS1002375043 (6:30145557 T>C), RS1002774432 (6:30146836 C>A), RS1003037388 (6:30142718 T>C), RS1004397841 (6:30135245 A>G), RS1004877538 (6:30140289 G>A,T), RS1004929178 (6:30146550 A>G), RS1004957967 (6:30139629 G>A), RS1004984716 (6:30146438 G>A), RS1005011002 (6:30134554 C>T), RS1005403147 (6:30136599 G>C,T)

Disease associations

OMIM: gene MIM:616976 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST002324_6	Anger	8.000000e-07
GCST004521_121	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_2	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_210	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_263	Autism spectrum disorder or schizophrenia	7.000000e-17
GCST004521_268	Autism spectrum disorder or schizophrenia	7.000000e-12
GCST004521_269	Autism spectrum disorder or schizophrenia	7.000000e-11
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_44	Autism spectrum disorder or schizophrenia	2.000000e-17
GCST004521_56	Autism spectrum disorder or schizophrenia	1.000000e-22
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_79	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST004599_233	Mean platelet volume	2.000000e-19
GCST005232_23	Neuroticism	8.000000e-09
GCST009325_89	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-08
GCST010002_46	Refractive error	2.000000e-20
GCST90002385_549	High light scatter reticulocyte count	1.000000e-25
GCST90002385_550	High light scatter reticulocyte count	2.000000e-12
GCST90002387_276	Immature fraction of reticulocytes	8.000000e-43
GCST90002395_432	Mean platelet volume	8.000000e-30
GCST90002402_728	Platelet count	1.000000e-25
GCST90002404_250	Red cell distribution width	8.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003015	aggressive behavior
EFO:0007660	neuroticism measurement
EFO:0007986	reticulocyte count
EFO:0004309	platelet count
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
bisphenol A	affects cotreatment, decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects methylation	1
Silicon Dioxide	increases expression	1
Sodium Hydroxide	affects response to substance	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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