ARIH2

Summary

ARIH2 (ariadne RBR E3 ubiquitin protein ligase 2, HGNC:690) is a protein-coding gene on chromosome 3p21.31, encoding E3 ubiquitin-protein ligase ARIH2 (O95376). E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3.

The protein encoded by this gene is an E3 ubiquitin-protein ligase that polyubiquitinates some proteins, tagging them for degradation. The encoded protein upregulates p53 in some cancer cells and may inhibit myelopoiesis. Several transcript variants encoding different isoforms have been found for this gene, although the full-length nature of some of them have not been determined yet.

Source: NCBI Gene 10425 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 65 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_006321

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:690
Approved symbol	ARIH2
Name	ariadne RBR E3 ubiquitin protein ligase 2
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	TRIAD1
Ensembl gene	ENSG00000177479
Ensembl biotype	protein_coding
OMIM	605615
Entrez	10425

Gene structure

Transcript identifiers

Ensembl transcripts: 88 — 64 protein_coding, 17 protein_coding_CDS_not_defined, 6 retained_intron, 1 nonsense_mediated_decay

ENST00000356401, ENST00000420814, ENST00000430423, ENST00000433170, ENST00000449376, ENST00000449729, ENST00000452385, ENST00000452882, ENST00000459976, ENST00000463204, ENST00000463738, ENST00000465217, ENST00000466850, ENST00000469038, ENST00000470296, ENST00000472640, ENST00000474618, ENST00000474936, ENST00000478224, ENST00000482342, ENST00000482427, ENST00000483333, ENST00000484999, ENST00000486316, ENST00000487891, ENST00000488963, ENST00000490095, ENST00000492077, ENST00000495507, ENST00000495761, ENST00000498314, ENST00000907507, ENST00000907508, ENST00000907509, ENST00000907510, ENST00000907511, ENST00000907512, ENST00000907513, ENST00000907514, ENST00000907515, ENST00000907516, ENST00000907517, ENST00000907518, ENST00000907519, ENST00000907520, ENST00000907521, ENST00000907522, ENST00000907523, ENST00000907524, ENST00000907525, ENST00000907526, ENST00000907527, ENST00000913578, ENST00000913579, ENST00000913580, ENST00000913581, ENST00000913582, ENST00000913583, ENST00000913584, ENST00000913585, ENST00000913586, ENST00000913587, ENST00000913588, ENST00000913589, ENST00000913590, ENST00000913591, ENST00000972215, ENST00000972216, ENST00000972217, ENST00000972218, ENST00000972219, ENST00000972220, ENST00000972221, ENST00000972222, ENST00000972223, ENST00000972224, ENST00000972225, ENST00000972226, ENST00000972227, ENST00000972228, ENST00000972229, ENST00000972230, ENST00000972231, ENST00000972232, ENST00000972233, ENST00000972234, ENST00000972235, ENST00000972236

RefSeq mRNA: 25 — MANE Select: NM_006321 NM_001317333, NM_001317334, NM_001349209, NM_001349210, NM_001349211, NM_001349212, NM_001349213, NM_001349214, NM_001349215, NM_001349216, NM_001349217, NM_001349218, NM_001349219, NM_001349220, NM_001349221, NM_001349222, NM_001349223, NM_001349224, NM_001349225, NM_001349226, NM_001349227, NM_001349228, NM_001349229, NM_001349230, NM_006321

CCDS: CCDS2780

Canonical transcript exons

ENST00000356401 — 16 exons

Exon	Start	End
ENSE00001304207	48922748	48922811
ENSE00001432170	48983199	48986382
ENSE00001820197	48918842	48918998
ENSE00003490361	48970595	48970704
ENSE00003503384	48981660	48981728
ENSE00003519053	48968534	48968655
ENSE00003551276	48927462	48927813
ENSE00003563871	48964919	48964982
ENSE00003573000	48980353	48980496
ENSE00003629005	48974958	48974979
ENSE00003635096	48982896	48982979
ENSE00003648179	48967125	48967275
ENSE00003649142	48979482	48979633
ENSE00003652984	48973699	48973816
ENSE00003688038	48974817	48974867
ENSE00003784944	48961612	48961679

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.8994 / max 225.7253, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36589	48.8741	1826
36590	0.0253	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.19	gold quality
gastrocnemius	UBERON:0001388	97.14	gold quality
muscle of leg	UBERON:0001383	97.05	gold quality
gluteal muscle	UBERON:0002000	97.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.69	gold quality
colonic epithelium	UBERON:0000397	96.68	gold quality
calcaneal tendon	UBERON:0003701	96.55	gold quality
monocyte	CL:0000576	96.45	gold quality
granulocyte	CL:0000094	96.39	gold quality
sural nerve	UBERON:0015488	96.32	gold quality
heart left ventricle	UBERON:0002084	96.21	gold quality
cardiac ventricle	UBERON:0002082	96.11	gold quality
right atrium auricular region	UBERON:0006631	96.03	gold quality
body of pancreas	UBERON:0001150	95.99	gold quality
rectum	UBERON:0001052	95.96	gold quality
leukocyte	CL:0000738	95.91	gold quality
mononuclear cell	CL:0000842	95.90	gold quality
triceps brachii	UBERON:0001509	95.74	gold quality
muscle organ	UBERON:0001630	95.65	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.52	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.47	gold quality
lower esophagus	UBERON:0013473	95.46	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.33	gold quality
heart	UBERON:0000948	95.29	gold quality
left lobe of thyroid gland	UBERON:0001120	95.28	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.27	gold quality
body of uterus	UBERON:0009853	95.25	gold quality
secondary oocyte	CL:0000655	95.24	gold quality
right lobe of thyroid gland	UBERON:0001119	95.23	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: no

Upstream regulators (CollecTRI, top): GFI1, HOXA10

miRNA regulators (miRDB)

126 targeting ARIH2, 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-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-204-5P	99.79	71.62	2439

Literature-anchored findings (GeneRIF, showing 14)

• proteasomal degradation of proteins that are ubiquitinated by Triad1 affects the clonogenic growth of primary myeloid progenitor cells (PMID:16118314)
• The fine-tuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis. (PMID:17646546)
• Triad1 has dual ubiquitin ligase activity; both its RING domains are crucial for inhibiting myeloid proliferation. The N-terminal RING finger (RING1) of Triad1 binds UbcH7; the C-terminal RING finger (RING2) binds Ubc13. (PMID:19340006)
• HoxA10 influences protein ubiquitination by activating transcription of ARIH2, the gene encoding Triad1 (PMID:21454682)
• In sharp contrast to SIAH1/SIAH2 and UBCH8, TRIAD1 binding to PML-RARalpha has no effect on its turnover. (PMID:22037423)
• TRIAD1 as a novel modulator of the p53-MDM2 axis that induces p53 activation by inhibiting its regulation by MDM2. (PMID:22819825)
• study demonstrated that TRIAD1 is a ubiquitination target for proteasome-dependent degradation by MDM2; results suggest TRIAD1 degradation by MDM2 suppresses TRIAD1-mediated cell growth; data suggested a novel negative regulatory mechanism of TRIAD1 via MDM2 E3 ligase ubiquitination (PMID:22940738)
• TRIAD1 and HHARI bind to and are activated by distinct neddylated Cullin-RING ligase complexes. (PMID:24076655)
• We show that ARIH2 E3-ligase regulates PABPN1 protein accumulation and aggregation (PMID:24486325)
• these findings reveal a novel mechanism of ubiquitination-dependent negative regulation of the NLRP3 inflammasome by ARIH2 and highlight ARIH2 as a potential therapeutic target for inflammatory diseases (PMID:29021376)
• Data found Mll-Ell increases Triad1 in a Hox-dependent manner. Triad1 antagonizes Mll-Ell-induced protein ubiquitination and progression to AML. Triad1 knockdown significantly shortened the latency to development of AML in mice transplanted with Mll-Ell-transduced bone marrow. Further results identify Triad1 as a leukemia suppressor in 11q23-AML. (PMID:29459712)
• ubiquitin-associated (UBA) domain-containing DCNL1 is monoubiquitylated when bound to CRLs and that this monoubiquitylation depends on the CRL-associated Ariadne RBR ligases TRIAD1 (ARIH2) and HHARI (ARIH1) and strictly requires the DCNL1’s UBA domain. (PMID:30587576)
• Here, using a quantitative proteomics approach, the authors identify the E3 ligase ARIH2 as a regulator of the HIV-1 Vif protein-dependent CRL5-mediated APOBEC3 degradation. The CUL5(Vif/CBFss) complex recruits ARIH2 where it acts to transfer ubiquitin directly to the APOBEC3 targets. (PMID:31253590)
• ARIH2 regulates the proliferation, DNA damage and chemosensitivity of gastric cancer cells by reducing the stability of p21 via ubiquitination. (PMID:35732617)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	arih2	ENSDARG00000012848
mus_musculus	Arih2	ENSMUSG00000064145
rattus_norvegicus	Arih2	ENSRNOG00000031827
drosophila_melanogaster	ari-2	FBGN0025186
caenorhabditis_elegans		WBGENE00020462

Paralogs (9): ANKIB1 (ENSG00000001629), RNF14 (ENSG00000013561), RNF19A (ENSG00000034677), RNF19B (ENSG00000116514), RNF144B (ENSG00000137393), RNF217 (ENSG00000146373), RNF144A (ENSG00000151692), ARIH1 (ENSG00000166233), PRKN (ENSG00000185345)

Protein

Protein identifiers

E3 ubiquitin-protein ligase ARIH2 — O95376 (reviewed: O95376)

Alternative names: Triad1 protein

All UniProt accessions (7): C9JAU2, C9JBC5, C9JCL4, C9JZ71, O95376, F8WCS4, Q6IBL8

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3. Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-5-RING ubiquitin ligase complex (ECS complex, also named CRL5 complex) and initiating ubiquitination of ECS substrates: associates with ECS complex and specifically mediates addition of the first ubiquitin on ECS targets. The initial ubiquitin is then elongated. E3 ubiquitin-protein ligase activity is activated upon binding to neddylated form of the cullin-5 (CUL5) component of the ECS complex. Together with the ECS(ASB9) complex, catalyzes ubiquitination of CKB. Promotes ubiquitination of DCUN1D1. Mediates ‘Lys-6’, ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination. May play a role in myelopoiesis. (Microbial infection) Following infection by HIV-1 virus, acts together with a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex) hijacked by the HIV-1 Vif protein, to catalyze ubiquitination and degradation of APOBEC3F and APOBEC3G.

Subunit / interactions. Interacts with (neddylated) CUL5; promoting association with cullin-5-RING ubiquitin ligase complexes (ECS complexes). Does not interact with other neddylated cullins (CUL1, CUL2, CUL3, CUL4A or CUL4B). Interacts (via RING-type zinc finger 1) with UBE2L3. Interacts (via RING-type zinc finger 2) with UBE2N. Interacts (via RING-type 2) with GFI1B. Interacts with GFI1; prevents its ubiquitination and proteasomal degradation.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed with higher expression in granulocytes.

Post-translational modifications. Ubiquitinated. Ubiquitination promotes proteasomal degradation.

Activity regulation. Autoinhibited by the ariadne domain, which masks the second RING-type zinc finger that contains the active site and inhibits the E3 activity. Inhibition is relieved upon binding to neddylated cullin-RING ubiquitin ligase complexes, which activate the E3 ligase activity of ARIH1.

Domain organisation. Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING-type zinc finger, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved active site Cys residue in the second RING-type zinc finger. The active site probably forms a thioester intermediate with ubiquitin taken from the active-site cysteine of the E2 before ultimately transferring it to a Lys residue on the substrate. The Ariadne domain inhibits activity by masking the second RING-type zinc finger that contains the active site.

Induction. Up-regulated by all-trans retinoic acid (ATRA). Up-regulated during differentiation of immature blood cells toward monocytes and granulocytes.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RBR family. Ariadne subfamily.

RefSeq proteins (25): NP_001304262, NP_001304263, NP_001336138, NP_001336139, NP_001336140, NP_001336141, NP_001336142, NP_001336143, NP_001336144, NP_001336145, NP_001336146, NP_001336147, NP_001336148, NP_001336149, NP_001336150, NP_001336151, NP_001336152, NP_001336153, NP_001336154, NP_001336155, NP_001336156, NP_001336157, NP_001336158, NP_001336159, NP_006312* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR002867	IBR_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR031127	E3_UB_ligase_RBR	Family
IPR044066	TRIAD_supradom	Domain
IPR045840	Ariadne	Domain
IPR047555	BRcat_RBR_TRIAD1	Domain
IPR047556	Rcat_RBR_TRIAD1	Domain

Pfam: PF00097, PF01485, PF19422, PF22191, PF26000

Enzyme classification (BRENDA):

• EC 2.3.2.31 — RBR-type E3 ubiquitin transferase (BRENDA: 4 organisms, 35 substrates, 4 inhibitors, 0 Km, 0 kcat entries)

UniProt features (87 total): binding site 24, helix 17, strand 13, mutagenesis site 11, turn 7, region of interest 4, zinc finger region 3, sequence variant 2, compositionally biased region 2, chain 1, active site 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7OD1	X-RAY DIFFRACTION	2.45
9T7V	ELECTRON MICROSCOPY	2.95
9SDX	ELECTRON MICROSCOPY	2.97
9SDY	ELECTRON MICROSCOPY	3.06
7ONI	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95376-F1	86.92	0.76

Functional residue map

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

Catalytic / active sites (1): 310

Ligand- & substrate-binding residues (24): 139; 142; 156; 158; 161; 164; 183; 188; 228; 233; 249; 252 …

Post-translational modifications (1): 353

Mutagenesis-validated functional residues (11):

Position	Phenotype
38	impaired ability to ubiquitinate proteins.
39	impaired ability to ubiquitinate proteins.
84–86	reduced interaction with neddylated cul5; when associated with a-100.
100	reduced interaction with neddylated cul5; when associated with 84-a–a-86.
158	loss of effect in myelopoiesis. abolishes interaction with ube2l3.
161	loss of effect in myelopoiesis.
257	does not affect interaction with ube2l3.
300	does not affect interaction with ube2l3.
310	abolishes e3 ubiquitin-protein ligase activity.
381–382	abolishes autoinhibition; when associated with a-455.
455	abolishes autoinhibition; when associated with 381-a-a-382.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 205 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, WANG_CLIM2_TARGETS_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_GROWTH, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, HUMMERICH_SKIN_CANCER_PROGRESSION_UP, GOBP_STEM_CELL_PROLIFERATION, MORF_TERF1, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_HEMATOPOIETIC_STEM_CELL_PROLIFERATION, MARTIN_VIRAL_GPCR_SIGNALING_DN

GO Biological Process (11): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), developmental cell growth (GO:0048588), protein K63-linked ubiquitination (GO:0070534), protein K48-linked ubiquitination (GO:0070936), hematopoietic stem cell proliferation (GO:0071425), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), innate immune response (GO:0045087), defense response to virus (GO:0051607)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Cul5-RING ubiquitin ligase complex (GO:0031466)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
protein polyubiquitination	2
cellular anatomical structure	2
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
cell growth	1
cell development	1
developmental growth	1
hemopoiesis	1
stem cell proliferation	1
immune response	1
defense response to symbiont	1
defense response	1
response to virus	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-like protein conjugating enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1234 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARIH2	CUL5	Q93034	910
ARIH2	RNF7	Q9UBF6	856
ARIH2	ELOB	Q15370	771
ARIH2	RING1	Q06587	730
ARIH2	MLLT10	P55197	723
ARIH2	LMO1	P25800	682
ARIH2	ASB7	Q9H672	652
ARIH2	KLHL20	Q9Y2M5	612
ARIH2	MARCHF7	Q9H992	612
ARIH2	ASB13	Q8WXK3	603
ARIH2	UBE2N	P61088	571
ARIH2	ELOC	Q15369	571
ARIH2	MGRN1	O60291	528
ARIH2	UBE3D	Q7Z6J8	524
ARIH2	FBXL2	Q9UKC9	522

IntAct

138 interactions, top by confidence:

A	B	Type	Score
ARIH2	UBE2L6	psi-mi:“MI:0915”(physical association)	0.880
UBE2L6	ARIH2	psi-mi:“MI:0915”(physical association)	0.880
ARIH2	UBE2L3	psi-mi:“MI:0915”(physical association)	0.880
CUL5	SOCS2	psi-mi:“MI:0914”(association)	0.880
UBE2L3	ARIH2	psi-mi:“MI:0915”(physical association)	0.880
ARIH2	UBE2L3	psi-mi:“MI:0914”(association)	0.880
UGP2	ARIH2	psi-mi:“MI:0915”(physical association)	0.780
ARIH2	UGP2	psi-mi:“MI:0915”(physical association)	0.780
BUB1	ARIH2	psi-mi:“MI:0915”(physical association)	0.740
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
TP53	ARIH2	psi-mi:“MI:0914”(association)	0.690
ARIH2	TP53	psi-mi:“MI:0915”(physical association)	0.690

BioGRID (409): ARIH2 (Two-hybrid), ARIH2 (Two-hybrid), ARIH2 (Affinity Capture-Western), PABPN1 (Affinity Capture-Western), ARIH2 (Affinity Capture-Western), ARIH2 (Two-hybrid), ARIH2 (Two-hybrid), ARIH2 (Two-hybrid), CCDC33 (Two-hybrid), UBE2L3 (Reconstituted Complex), TCEB2 (Affinity Capture-Western), TCEB1 (Affinity Capture-Western), CUL5 (Reconstituted Complex), ARIH2 (Affinity Capture-MS), ARIH2 (Affinity Capture-MS)

ESM2 similar proteins: A9JTG5, B6DMK2, E0X9N4, F1RB95, O00463, O01965, O60678, O70467, O75417, O76924, O95376, P0C8K8, P39429, P70191, Q12933, Q14AI0, Q22431, Q4U5R4, Q5NU13, Q5XI55, Q5ZIJ9, Q5ZJM3, Q6GLD9, Q6J1I8, Q6J212, Q6J2U6, Q7Z569, Q84RR0, Q8CGS6, Q8L829, Q8VIL2, Q8W468, Q922H1, Q95K79, Q96BT7, Q96IV0, Q99MP8, Q9BVC3, Q9DFG8, Q9ERV1

Diamond homologs: A2VEA3, A5PK27, B1H1E4, O01965, O76924, O95376, P0C8K8, P36113, P50876, Q22431, Q32NS4, Q54CX4, Q5UQ35, Q6NW85, Q6PFJ9, Q6T486, Q7Z419, Q84RQ8, Q84RR0, Q84RR2, Q8BKD6, Q8L829, Q8W468, Q925F3, Q94981, Q949V6, Q9C5A4, Q9LVW9, Q9LVX0, Q9P3U4, Q9SKC2, Q9SKC3, Q9SKC4, Q9Y4X5, Q9Z1K5, Q9Z1K6, Q5RFV4, Q6DH94, D3YYI7, F4KGU4

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CUL5	“up-regulates activity”	ARIH2	binding
Ub:E2	“up-regulates activity”	ARIH2	ubiquitination
ARIH2	“up-regulates activity”	NLRP3	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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	8	45.3×	1e-09
E3 ubiquitin ligases ubiquitinate target proteins	5	14.9×	1e-03
Antigen processing: Ubiquitination & Proteasome degradation	18	10.3×	3e-11
Neddylation	11	8.0×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	7	37.1×	1e-07
protein monoubiquitination	6	27.9×	8e-06
protein K63-linked ubiquitination	6	21.7×	3e-05
protein K48-linked ubiquitination	9	20.5×	1e-07
protein polyubiquitination	12	18.7×	6e-10
ubiquitin-dependent protein catabolic process	13	13.0×	4e-09
protein ubiquitination	17	9.5×	6e-10
proteasome-mediated ubiquitin-dependent protein catabolic process	12	8.5×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	42
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3246860	NC_000003.11:g.(?48895143)(49213234_?)del	Pathogenic
2692232	NM_006321.4(ARIH2):c.1411-3C>T	Likely pathogenic

SpliceAI

2546 predictions. Top by Δscore:

Variant	Effect	Δscore
3:48918998:GGTA:G	donor_loss	1.0000
3:48918999:G:GG	donor_gain	1.0000
3:48918999:G:T	donor_loss	1.0000
3:48919000:T:A	donor_loss	1.0000
3:48964916:TAGAT:T	acceptor_loss	1.0000
3:48964917:A:AG	acceptor_gain	1.0000
3:48964918:G:GG	acceptor_gain	1.0000
3:48964918:GAT:G	acceptor_gain	1.0000
3:48964978:AACAT:A	donor_gain	1.0000
3:48964979:ACAT:A	donor_gain	1.0000
3:48964979:ACATG:A	donor_loss	1.0000
3:48964980:CATGT:C	donor_loss	1.0000
3:48964981:AT:A	donor_gain	1.0000
3:48964981:ATGTG:A	donor_loss	1.0000
3:48964982:TGTG:T	donor_loss	1.0000
3:48964983:G:GG	donor_gain	1.0000
3:48964983:GTGA:G	donor_loss	1.0000
3:48964984:T:TC	donor_loss	1.0000
3:48964985:G:GT	donor_loss	1.0000
3:48967121:CCAG:C	acceptor_loss	1.0000
3:48967122:CAG:C	acceptor_loss	1.0000
3:48967123:A:T	acceptor_loss	1.0000
3:48967124:G:A	acceptor_loss	1.0000
3:48967275:GGTG:G	donor_loss	1.0000
3:48967276:G:T	donor_loss	1.0000
3:48967277:T:G	donor_loss	1.0000
3:48970581:T:A	acceptor_gain	1.0000
3:48970593:A:AG	acceptor_gain	1.0000
3:48970594:G:GG	acceptor_gain	1.0000
3:48970594:GA:G	acceptor_gain	1.0000

AlphaMissense

3305 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:48961654:T:A	W100R	1.000
3:48961654:T:C	W100R	1.000
3:48967152:T:C	C139R	1.000
3:48967227:T:C	C164R	1.000
3:48967229:C:G	C164W	1.000
3:48967230:T:A	W165R	1.000
3:48967230:T:C	W165R	1.000
3:48967232:G:C	W165C	1.000
3:48967232:G:T	W165C	1.000
3:48968542:T:C	C183R	1.000
3:48968543:G:A	C183Y	1.000
3:48968544:C:G	C183W	1.000
3:48970616:T:A	C228S	1.000
3:48970616:T:C	C228R	1.000
3:48970617:G:C	C228S	1.000
3:48970631:T:C	C233R	1.000
3:48970633:C:G	C233W	1.000
3:48970679:T:C	C249R	1.000
3:48970703:T:C	C257R	1.000
3:48970704:G:A	C257Y	1.000
3:48973699:T:G	C257W	1.000
3:48973706:T:C	C260R	1.000
3:48973721:C:G	H265D	1.000
3:48973723:C:A	H265Q	1.000
3:48973723:C:G	H265Q	1.000
3:48973727:C:T	P267S	1.000
3:48973728:C:A	P267H	1.000
3:48973728:C:G	P267R	1.000
3:48973736:T:A	C270S	1.000
3:48973736:T:C	C270R	1.000

dbSNP variants (sampled 300 via entrez): RS1000051643 (3:48942715 G>A), RS1000120498 (3:48954228 G>A), RS1000124074 (3:48929174 G>A), RS1000169002 (3:48933995 C>G), RS1000210837 (3:48958831 A>G), RS1000280255 (3:48955188 A>C,G), RS1000442850 (3:48940383 T>C), RS1000496894 (3:48920494 T>C), RS1000565869 (3:48980686 A>G), RS1000627437 (3:48973394 G>A,T), RS1000646023 (3:48949262 C>T), RS1000730712 (3:48940166 A>G), RS1000731654 (3:48953647 C>T), RS1000816032 (3:48960156 A>G), RS1000844553 (3:48917232 C>G)

Disease associations

OMIM: gene MIM:605615 | disease phenotypes: MIM:212138

GenCC curated gene-disease

Mondo (3): myoepithelial tumor (MONDO:0002380), autism spectrum disorder (MONDO:0005258), carnitine-acylcarnitine translocase deficiency (MONDO:0008918)

Orphanet (2): Carnitine-acylcarnitine translocase deficiency (Orphanet:159), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST004624_44	Sum eosinophil basophil counts	2.000000e-10
GCST006624_76	Systolic blood pressure	3.000000e-10
GCST007294_107	Body fat distribution (trunk fat ratio)	9.000000e-06
GCST007294_72	Body fat distribution (trunk fat ratio)	1.000000e-18
GCST007294_98	Body fat distribution (trunk fat ratio)	3.000000e-15
GCST007295_21	Body fat distribution (leg fat ratio)	8.000000e-06
GCST007295_45	Body fat distribution (leg fat ratio)	1.000000e-10
GCST007295_80	Body fat distribution (leg fat ratio)	1.000000e-14
GCST007565_83	Morning person	1.000000e-16
GCST008162_9	Hip circumference	2.000000e-06
GCST010002_422	Refractive error	4.000000e-14
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST012490_301	Femur bone mineral density x serum urate levels interaction	8.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0006335	systolic blood pressure
EFO:0004341	body fat distribution
EFO:0008328	chronotype measurement
EFO:0004346	neuroimaging measurement
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585
C562812	Carnitine-Acylcarnitine Translocase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
bisphenol A	affects expression, decreases methylation, affects cotreatment, decreases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Silicon Dioxide	increases expression, decreases expression	2
bisphenol F	affects cotreatment, decreases methylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	increases expression	1
deguelin	increases expression	1
ICG 001	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
pyrachlostrobin	increases expression	1
bisphenol S	affects cotreatment, decreases expression	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
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Arsenic	affects expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Dieldrin	decreases response to substance	1
Folic Acid	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7KD	Ubigene A-549 ARIH2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder