HECTD2

Summary

HECTD2 (HECT domain E3 ubiquitin protein ligase 2, HGNC:26736) is a protein-coding gene on chromosome 10q23.32, encoding Probable E3 ubiquitin-protein ligase HECTD2 (Q5U5R9). E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein polyubiquitination. Predicted to be located in cytosol.

Source: NCBI Gene 143279 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 81 total
• MANE Select transcript: NM_182765

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26736
Approved symbol	HECTD2
Name	HECT domain E3 ubiquitin protein ligase 2
Location	10q23.32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ37306
Ensembl gene	ENSG00000165338
Ensembl biotype	protein_coding
OMIM	620876
Entrez	143279

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000298068, ENST00000371667, ENST00000371681, ENST00000446394, ENST00000498446, ENST00000631422

RefSeq mRNA: 4 — MANE Select: NM_182765 NM_001284274, NM_001348365, NM_173497, NM_182765

CCDS: CCDS60591, CCDS7414, CCDS7415

Canonical transcript exons

ENST00000298068 — 21 exons

Exon	Start	End
ENSE00001092210	91500502	91500617
ENSE00001092216	91498872	91498959
ENSE00001092219	91501191	91501334
ENSE00001092221	91499044	91499150
ENSE00001198135	91498108	91498182
ENSE00001198144	91512264	91514820
ENSE00001299682	91492352	91492484
ENSE00001305896	91496214	91496372
ENSE00001330690	91493420	91493508
ENSE00001338170	91487682	91487778
ENSE00001881111	91410344	91410576
ENSE00002478213	91462095	91462184
ENSE00002486337	91461254	91461356
ENSE00002535693	91460427	91460565
ENSE00003537490	91484507	91484655
ENSE00003593857	91485180	91485303
ENSE00003595529	91425281	91425410
ENSE00003606334	91482967	91483076
ENSE00003656609	91491200	91491307
ENSE00003662834	91478201	91478265
ENSE00003666369	91481094	91481139

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 93.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1603 / max 132.6556, expressed in 1711 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106218	8.8550	1657
106215	1.7870	904
106216	0.5183	257

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.21	gold quality
endothelial cell	CL:0000115	91.78	gold quality
tibia	UBERON:0000979	91.01	gold quality
seminal vesicle	UBERON:0000998	90.90	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.34	gold quality
tendon	UBERON:0000043	88.96	gold quality
oviduct epithelium	UBERON:0004804	88.02	gold quality
cauda epididymis	UBERON:0004360	87.77	gold quality
secondary oocyte	CL:0000655	87.61	gold quality
cartilage tissue	UBERON:0002418	87.48	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.36	gold quality
cortical plate	UBERON:0005343	86.00	gold quality
smooth muscle tissue	UBERON:0001135	85.93	gold quality
parietal pleura	UBERON:0002400	85.84	gold quality
popliteal artery	UBERON:0002250	85.54	gold quality
tibial artery	UBERON:0007610	85.53	gold quality
epithelial cell of pancreas	CL:0000083	85.44	gold quality
descending thoracic aorta	UBERON:0002345	85.42	gold quality
layer of synovial tissue	UBERON:0007616	85.38	gold quality
aorta	UBERON:0000947	85.36	gold quality
ascending aorta	UBERON:0001496	85.30	gold quality
thoracic aorta	UBERON:0001515	85.24	gold quality
visceral pleura	UBERON:0002401	85.13	gold quality
germinal epithelium of ovary	UBERON:0001304	85.01	gold quality
artery	UBERON:0001637	84.91	gold quality
oocyte	CL:0000023	84.82	gold quality
embryo	UBERON:0000922	84.68	gold quality
ganglionic eminence	UBERON:0004023	84.68	gold quality
left ovary	UBERON:0002119	84.35	gold quality
tendon of biceps brachii	UBERON:0008188	84.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

267 targeting HECTD2, 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-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
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-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772

Literature-anchored findings (GeneRIF, showing 7)

• HECTD2 haplotypes are associated with the susceptibility to human prion diseases. (PMID:19214206)
• The common haplotypes of HECTD2, tagged by rs12249854, are not associated with susceptibility to late onset Alzheimer’s disease (PMID:19754925)
• HECTD2 polymorphisms are not associated with genetic susceptibility to sporadic Creutzfeldt-Jakob disease in a Korean population (PMID:21335971)
• A major biological consequence of upregulation of miR-221 is reprogramming of androgen receptor signaling via downregulation of HECTD2 and RAB1A. (PMID:23770851)
• E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion. (PMID:34145398)
• Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer. (PMID:34972816)
• HECTD2/TNFAIP1 Axis Regulating the p38/JNK Pathway to Promote an Inflammatory Response in Renal Cell Carcinoma Cells. (PMID:38688591)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hectd2	ENSDARG00000061194
mus_musculus	Hectd2	ENSMUSG00000041180
rattus_norvegicus	Hectd2	ENSRNOG00000056753

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

Probable E3 ubiquitin-protein ligase HECTD2 — Q5U5R9 (reviewed: Q5U5R9)

Alternative names: HECT domain-containing protein 2, HECT-type E3 ubiquitin transferase HECTD2

All UniProt accessions (4): A0A0J9YVV1, E7ERR3, Q5U5R9, X6R824

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. (Microbial infection) Catalyzes ubiquitination of Botulinum neurotoxin A light chain (LC) of C.botulinum neurotoxin type A (BoNT/A).

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5U5R9-1	1	yes
Q5U5R9-2	2

RefSeq proteins (4): NP_001271203, NP_001335294, NP_775768, NP_877497* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000569	HECT_dom	Domain
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR044611	E3A/B/C-like	Family

Pfam: PF00632

UniProt features (13 total): sequence conflict 3, compositionally biased region 2, splice variant 2, chain 1, domain 1, region of interest 1, active site 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5U5R9-F1	81.31	0.61

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): 744 (glycyl thioester intermediate)

Post-translational modifications (1): 9

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 243 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, AAGTCCA_MIR422B_MIR422A, ATACCTC_MIR202, TGACCTY_ERR1_Q2, CAGCTG_AP4_Q5, EVI1_05, GTGCCTT_MIR506, TCF11_01, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, AACTTT_UNKNOWN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN

GO Biological Process (2): protein polyubiquitination (GO:0000209), protein ubiquitination (GO:0016567)

GO Molecular Function (3): ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), transferase activity (GO:0016740)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	1
protein modification by small protein conjugation	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

166 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HECTD2	RNF8	O76064	462
HECTD2	UBE2N	P61088	447
HECTD2	PRR20A	P86496	434
HECTD2	ZNF688	P0C7X2	400
HECTD2	RAB1A	P11476	367
HECTD2	NOC3L	Q8WTT2	348
HECTD2	FAM184A	Q8NB25	336
HECTD2	CCDC85C	A6NKD9	332
HECTD2	ACBD7	Q8N6N7	321
HECTD2	TSGA10	Q9BZW7	282
HECTD2	PLCE1	Q9P212	273
HECTD2	FAXDC2	Q96IV6	254
HECTD2	DAZAP1	Q96EP5	230
HECTD2	HGD	Q93099	224
HECTD2	NAPG	Q99747	224

IntAct

6 interactions, top by confidence:

A	B	Type	Score
RNF166	MPDZ	psi-mi:“MI:0914”(association)	0.530
HECTD2	CALR	psi-mi:“MI:0915”(physical association)	0.400
HECTD2	HSPA8	psi-mi:“MI:0915”(physical association)	0.400
ACKR3	MRPL4	psi-mi:“MI:0914”(association)	0.350
BTG3	HECTD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): HECTD2 (Affinity Capture-MS), HECTD2 (Affinity Capture-MS), PIAS1 (Affinity Capture-Western), PIAS1 (Biochemical Activity), HECTD2 (Affinity Capture-Western), HECTD2 (Protein-peptide), HECTD2 (Affinity Capture-MS), HECTD2 (Affinity Capture-MS), HECTD2 (Reconstituted Complex), HECTD2 (Proximity Label-MS), HSPA8 (Affinity Capture-MS), HECTD2 (Two-hybrid), HECTD2 (Affinity Capture-MS), HECTD2 (Co-fractionation), KEAP1 (Affinity Capture-MS)

ESM2 similar proteins: A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4GEU5, B8N7E5, G0S9J5, G5ECY0, H2L056, O00308, O14326, O42643, P10823, P39055, P39940, P46935, Q0CCL1, Q2TAS2, Q2UBP1, Q45FX5, Q4WTF3, Q5BDP1, Q5RBF2, Q5RD78, Q5U5R9, Q62940, Q757T0, Q8BZZ3, Q8C863, Q8CFI0, Q92462, Q96J02, Q96PU5, Q9CUN6, Q9DBH0, Q9H0M0, Q9HAU4, Q9HCE7

Diamond homologs: A0A8C0NGY6, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	HECTD2	ubiquitination
HECTD2	“down-regulates quantity by destabilization”	PIAS1	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3523 predictions. Top by Δscore:

Variant	Effect	Δscore
10:91410574:GCG:G	donor_gain	1.0000
10:91410576:GGTA:G	donor_loss	1.0000
10:91410577:G:GG	donor_gain	1.0000
10:91410578:T:G	donor_loss	1.0000
10:91425279:AG:A	acceptor_gain	1.0000
10:91425280:GG:G	acceptor_gain	1.0000
10:91425406:GAATG:G	donor_gain	1.0000
10:91425407:AATGG:A	donor_loss	1.0000
10:91425408:ATGG:A	donor_loss	1.0000
10:91425409:TGG:T	donor_loss	1.0000
10:91425410:GGTAA:G	donor_loss	1.0000
10:91425411:G:T	donor_loss	1.0000
10:91425412:T:A	donor_loss	1.0000
10:91460416:A:AG	acceptor_gain	1.0000
10:91460417:T:G	acceptor_gain	1.0000
10:91460418:A:AG	acceptor_gain	1.0000
10:91460419:C:G	acceptor_gain	1.0000
10:91460423:A:AG	acceptor_gain	1.0000
10:91460423:ACAGT:A	acceptor_gain	1.0000
10:91460424:CAGTG:C	acceptor_gain	1.0000
10:91460425:A:AG	acceptor_gain	1.0000
10:91460425:AGT:A	acceptor_gain	1.0000
10:91460425:AGTGA:A	acceptor_gain	1.0000
10:91460426:G:GA	acceptor_gain	1.0000
10:91460426:GT:G	acceptor_gain	1.0000
10:91460426:GTG:G	acceptor_gain	1.0000
10:91460426:GTGA:G	acceptor_gain	1.0000
10:91460426:GTGAG:G	acceptor_gain	1.0000
10:91460561:TTTCA:T	donor_gain	1.0000
10:91460562:TTCA:T	donor_gain	1.0000

AlphaMissense

5121 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:91492397:T:C	F449L	1.000
10:91492399:T:A	F449L	1.000
10:91492399:T:G	F449L	1.000
10:91492442:T:A	W464R	1.000
10:91492442:T:C	W464R	1.000
10:91493503:G:A	G506R	1.000
10:91493503:G:C	G506R	1.000
10:91493504:G:A	G506E	1.000
10:91498939:T:A	V608D	1.000
10:91484619:T:A	W312R	0.999
10:91484619:T:C	W312R	0.999
10:91487692:T:C	C369R	0.999
10:91487726:A:T	K380I	0.999
10:91487727:A:C	K380N	0.999
10:91487727:A:T	K380N	0.999
10:91487749:T:C	S388P	0.999
10:91487759:A:C	Q391P	0.999
10:91487763:G:A	M392I	0.999
10:91487763:G:C	M392I	0.999
10:91487763:G:T	M392I	0.999
10:91491207:T:C	L400P	0.999
10:91491254:T:C	F416L	0.999
10:91491256:T:A	F416L	0.999
10:91491256:T:G	F416L	0.999
10:91492386:T:C	L445S	0.999
10:91492392:T:A	V447D	0.999
10:91492398:T:C	F449S	0.999
10:91492418:G:C	D456H	0.999
10:91492419:A:C	D456A	0.999
10:91492419:A:T	D456V	0.999

dbSNP variants (sampled 300 via entrez): RS1000018277 (10:91420328 G>A), RS1000019188 (10:91480561 A>G), RS1000031444 (10:91490771 G>A,C), RS1000043372 (10:91446237 G>A,T), RS1000146243 (10:91467531 G>A,T), RS1000297186 (10:91467742 T>C), RS1000306951 (10:91474481 A>G), RS1000323812 (10:91482090 G>A), RS1000367416 (10:91482428 G>A), RS1000420323 (10:91500038 T>G), RS1000427625 (10:91474867 T>C), RS1000465490 (10:91421530 T>G), RS1000471925 (10:91431937 G>A), RS1000502350 (10:91459778 C>T), RS1000564031 (10:91467478 G>C,T)

Disease associations

OMIM: gene MIM:620876 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009758_4	Idiopathic pulmonary fibrosis	6.000000e-07
GCST011878_15	Mitochondrial heteroplasmy measurement	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0600008	mitochondrial heteroplasmy measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects expression	4
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenite	increases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
pyrimidifen	increases expression	1
clothianidin	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
Bortezomib	increases expression	1
Irinotecan	decreases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression	1
Estradiol	increases expression, affects cotreatment	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Quercetin	decreases expression	1
Thimerosal	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Oxyquinoline	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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