HERC6

Summary

HERC6 (HECT and RLD domain containing E3 ubiquitin protein ligase family member 6, HGNC:26072) is a protein-coding gene on chromosome 4q22.1, encoding Probable E3 ubiquitin-protein ligase HERC6 (Q8IVU3). 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.

HERC6 belongs to the HERC family of ubiquitin ligases, all of which contain a HECT domain and at least 1 RCC1 (MIM 179710)-like domain (RLD). The 350-amino acid HECT domain is predicted to catalyze the formation of a thioester with ubiquitin before transferring it to a substrate, and the RLD is predicted to act as a guanine nucleotide exchange factor for small G proteins (Hochrainer et al., 2005 [PubMed 15676274]).

Source: NCBI Gene 55008 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 97 total
• MANE Select transcript: NM_017912

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26072
Approved symbol	HERC6
Name	HECT and RLD domain containing E3 ubiquitin protein ligase family member 6
Location	4q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20637
Ensembl gene	ENSG00000138642
Ensembl biotype	protein_coding
OMIM	609249
Entrez	55008

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000264346, ENST00000380265, ENST00000502870, ENST00000504905, ENST00000506714, ENST00000506842, ENST00000515365, ENST00000896954, ENST00000896955, ENST00000896956, ENST00000896957, ENST00000955919, ENST00000955920

RefSeq mRNA: 2 — MANE Select: NM_017912 NM_001165136, NM_017912

CCDS: CCDS47098, CCDS54777

Canonical transcript exons

ENST00000264346 — 23 exons

Exon	Start	End
ENSE00000969964	88417425	88417579
ENSE00000969968	88423860	88423973
ENSE00001006118	88404876	88404997
ENSE00002067157	88378852	88379120
ENSE00002435456	88437711	88437781
ENSE00002443527	88435725	88435891
ENSE00002446054	88413077	88413266
ENSE00002478882	88431162	88431305
ENSE00002491551	88436905	88436971
ENSE00002496710	88439874	88440057
ENSE00002499346	88405554	88405613
ENSE00002504832	88440148	88440250
ENSE00002526115	88408524	88408617
ENSE00002527883	88424595	88424702
ENSE00002529944	88428580	88428750
ENSE00003498590	88385499	88385575
ENSE00003514700	88396851	88396987
ENSE00003531191	88383221	88383380
ENSE00003565924	88390652	88390879
ENSE00003580712	88398142	88398209
ENSE00003600376	88393488	88393582
ENSE00003607992	88396015	88396142
ENSE00003901977	88442234	88443097

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 95.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.3612 / max 1184.2693, expressed in 1395 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48803	4.1053	1266
48800	1.4950	442
48806	1.3553	43
48802	0.5231	207
48799	0.4645	210
48805	0.4524	35
48798	0.4487	140
48801	0.3548	142
48804	0.1621	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.75	gold quality
palpebral conjunctiva	UBERON:0001812	93.72	gold quality
oocyte	CL:0000023	91.51	gold quality
lower esophagus mucosa	UBERON:0035834	87.00	gold quality
esophagus squamous epithelium	UBERON:0006920	86.66	gold quality
esophagus mucosa	UBERON:0002469	86.31	gold quality
epithelium of esophagus	UBERON:0001976	86.22	gold quality
penis	UBERON:0000989	85.70	gold quality
gall bladder	UBERON:0002110	85.08	gold quality
nasal cavity epithelium	UBERON:0005384	84.43	gold quality
decidua	UBERON:0002450	84.21	gold quality
apex of heart	UBERON:0002098	83.46	gold quality
squamous epithelium	UBERON:0006914	83.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.92	gold quality
islet of Langerhans	UBERON:0000006	82.85	gold quality
right uterine tube	UBERON:0001302	82.61	gold quality
amniotic fluid	UBERON:0000173	82.53	gold quality
ectocervix	UBERON:0012249	82.41	gold quality
granulocyte	CL:0000094	82.34	gold quality
vagina	UBERON:0000996	82.24	gold quality
oral cavity	UBERON:0000167	81.38	gold quality
germinal epithelium of ovary	UBERON:0001304	81.34	gold quality
pancreatic ductal cell	CL:0002079	81.24	silver quality
primary visual cortex	UBERON:0002436	80.98	gold quality
leukocyte	CL:0000738	80.79	gold quality
nasal cavity mucosa	UBERON:0001826	80.75	gold quality
monocyte	CL:0000576	80.64	gold quality
mononuclear cell	CL:0000842	80.54	gold quality
ventricular zone	UBERON:0003053	80.54	gold quality
esophagus	UBERON:0001043	80.39	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	366.41
E-ANND-3	no	5.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting HERC6, 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-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-664A-3P	99.22	71.08	2696
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-10A-5P	98.89	69.85	712
HSA-MIR-10B-5P	98.89	69.86	711
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-581	98.39	67.42	835
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-12127	97.93	66.67	793
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-3691-3P	97.90	65.97	791

Literature-anchored findings (GeneRIF, showing 1)

• HERC6 ancestor emerged in nematodes and that the family expanded throughout evolution. The mRNA expression pattern was found to be diverse in selected tissues and cells (PMID:15676274)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Herc6	ENSMUSG00000029798
rattus_norvegicus	Herc6	ENSRNOG00000023969

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), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

Probable E3 ubiquitin-protein ligase HERC6 — Q8IVU3 (reviewed: Q8IVU3)

Alternative names: HECT domain and RCC1-like domain-containing protein 6, HECT-type E3 ubiquitin transferase HERC6

All UniProt accessions (3): Q8IVU3, D6RCT4, H0Y9U0

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.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Detected in brain, heart, placenta and testis.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Major transcript. Minor transcript. Minor transcript.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IVU3-1	1	yes
Q8IVU3-2	2
Q8IVU3-3	3

RefSeq proteins (2): NP_001158608, NP_060382* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR000569	HECT_dom	Domain
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR051709	Ub-ligase/GTPase-reg	Family
IPR058923	RCC1-like_dom	Domain

Pfam: PF00632, PF25390

UniProt features (23 total): repeat 5, helix 5, sequence variant 4, splice variant 3, strand 2, chain 1, sequence conflict 1, domain 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5W87	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IVU3-F1	86.55	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.

Catalytic / active sites (1): 985 (glycyl thioester intermediate)

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 221 (showing top): AGGAAGC_MIR5163P, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOZGIT_ESR1_TARGETS_DN, AAGCCAT_MIR135A_MIR135B, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, DOANE_RESPONSE_TO_ANDROGEN_DN, ATTACAT_MIR3803P, DAUER_STAT3_TARGETS_DN, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, DOUGLAS_BMI1_TARGETS_DN

GO Biological Process (4): hematopoietic progenitor cell differentiation (GO:0002244), ubiquitin-dependent protein catabolic process (GO:0006511), response to bacterium (GO:0009617), 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 (3): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), 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
cellular anatomical structure	3
hemopoiesis	1
cell differentiation	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
response to other organism	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
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

718 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HERC6	ISG15	P05161	747
HERC6	UBE2L6	O14933	661
HERC6	UBA7	P41226	636
HERC6	IRF9	Q00978	583
HERC6	IFI44	Q8TCB0	578
HERC6	USP18	Q9UMW8	569
HERC6	RSAD2	Q8WXG1	560
HERC6	DDX60	Q8IY21	539
HERC6	RTP4	Q96DX8	533
HERC6	OAS2	P29728	529
HERC6	MX1	P20591	512
HERC6	OAS3	Q9Y6K5	498
HERC6	IFIT1	P09914	487
HERC6	RABIF	P47224	486
HERC6	IFI6	P09912	479

IntAct

5 interactions, top by confidence:

A	B	Type	Score
HERC6	UBE2L6	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	HERC6	psi-mi:“MI:0915”(physical association)	0.400
LATS2	WTIP	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350

BioGRID (18): HERC6 (Affinity Capture-MS), HERC6 (Biochemical Activity), UBE2L3 (Reconstituted Complex), UBE2L6 (Affinity Capture-MS), HERC6 (Reconstituted Complex), HERC6 (Affinity Capture-MS), HERC6 (Synthetic Lethality), HERC6 (Proximity Label-MS), HERC6 (Affinity Capture-MS), UBE2L6 (Affinity Capture-MS), HERC3 (Affinity Capture-Western), HERC4 (Affinity Capture-Western), UBQLN2 (Affinity Capture-Western), NME2 (Two-hybrid), HERC6 (Affinity Capture-MS)

ESM2 similar proteins: B1ARD6, B1ARD8, C0IN03, C6FG12, F1M649, F1MHT9, F2Z461, G1SRW8, O95786, P09913, P0C7P3, Q08AF3, Q2EMV9, Q2TB18, Q3UP24, Q460N5, Q5K651, Q5RCY5, Q5RCZ8, Q5U311, Q5XHI4, Q61098, Q68D06, Q692V3, Q69Z37, Q6IEE8, Q6P2S7, Q6P3V7, Q6P5U7, Q6P6V7, Q6Q899, Q6QR59, Q7Z7L1, Q86VS3, Q8BIR2, Q8CAS9, Q8CBA2, Q8IVG5, Q8IVU3, Q8IXQ6

Diamond homologs: A6NED2, F1RD40, F2Z461, O74881, O75592, O95714, P18754, P23800, Q15034, Q4R828, Q4U2R1, Q52KW8, Q5GLZ8, Q5PQN1, Q6NRS1, Q6PAV2, Q7TPH6, Q80YD6, Q8BTU7, Q8IVU3, Q8VE37, Q9FN03, Q9NB71, Q9P2D0, Q9UII4, D3ZGQ5, O95199, P0C5Y8, P25171, P25183, P58544, Q15751, Q5BIW4, Q5DX34, Q5RCZ7, Q6NXM2, Q6NYE2, Q6ZPR6, Q7ZZC8, Q86SG6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	HERC6	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3287 predictions. Top by Δscore:

Variant	Effect	Δscore
4:88385493:TTATA:T	acceptor_loss	1.0000
4:88385494:TATAG:T	acceptor_loss	1.0000
4:88385495:ATAGG:A	acceptor_loss	1.0000
4:88385496:TA:T	acceptor_loss	1.0000
4:88385497:A:AG	acceptor_gain	1.0000
4:88385497:AGG:A	acceptor_loss	1.0000
4:88385498:G:A	acceptor_loss	1.0000
4:88385498:G:GG	acceptor_gain	1.0000
4:88385575:GGTA:G	donor_loss	1.0000
4:88385576:GTAAG:G	donor_loss	1.0000
4:88393486:A:AG	acceptor_gain	1.0000
4:88393487:G:GG	acceptor_gain	1.0000
4:88396005:T:TA	acceptor_gain	1.0000
4:88396009:A:AG	acceptor_gain	1.0000
4:88396010:A:AG	acceptor_gain	1.0000
4:88396010:AGCAG:A	acceptor_gain	1.0000
4:88396011:G:GA	acceptor_gain	1.0000
4:88396011:GCA:G	acceptor_gain	1.0000
4:88396011:GCAGG:G	acceptor_gain	1.0000
4:88396012:CAGG:C	acceptor_loss	1.0000
4:88396013:AG:A	acceptor_gain	1.0000
4:88396013:AGGA:A	acceptor_loss	1.0000
4:88396014:G:GA	acceptor_loss	1.0000
4:88396014:G:GC	acceptor_gain	1.0000
4:88396014:GG:G	acceptor_gain	1.0000
4:88396014:GGA:G	acceptor_gain	1.0000
4:88396138:GGAAG:G	donor_gain	1.0000
4:88396139:GAAGG:G	donor_gain	1.0000
4:88396140:A:T	donor_gain	1.0000
4:88396140:AAGGT:A	donor_loss	1.0000

AlphaMissense

6772 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:88390792:A:C	S193R	0.994
4:88390794:C:A	S193R	0.994
4:88390794:C:G	S193R	0.994
4:88390669:T:A	W152R	0.989
4:88390669:T:C	W152R	0.989
4:88390828:T:A	W205R	0.989
4:88390828:T:C	W205R	0.989
4:88383316:T:A	W99R	0.983
4:88383316:T:C	W99R	0.983
4:88439941:T:C	F875L	0.977
4:88439943:T:A	F875L	0.977
4:88439943:T:G	F875L	0.977
4:88393568:G:C	A249P	0.975
4:88385557:T:C	S140P	0.974
4:88436966:T:C	F827L	0.974
4:88436968:T:A	F827L	0.974
4:88436968:T:G	F827L	0.974
4:88390799:C:A	A195D	0.970
4:88431291:T:A	W746R	0.970
4:88431291:T:C	W746R	0.970
4:88385561:T:C	L141P	0.967
4:88385564:C:A	A142E	0.966
4:88440040:T:A	W908R	0.966
4:88440040:T:C	W908R	0.966
4:88390672:G:A	G153R	0.965
4:88390672:G:C	G153R	0.965
4:88383280:T:C	S87P	0.964
4:88396033:T:C	F260L	0.964
4:88396035:T:A	F260L	0.964
4:88396035:T:G	F260L	0.964

dbSNP variants (sampled 300 via entrez): RS1000068831 (4:88386052 C>T), RS1000074283 (4:88430946 T>C,G), RS1000097218 (4:88392467 G>A), RS1000144060 (4:88379444 T>C,G), RS1000228599 (4:88382493 C>T), RS1000260839 (4:88433277 G>A,T), RS1000296955 (4:88386458 G>C), RS1000344741 (4:88398751 T>C), RS10003728 (4:88377049 G>A,T), RS1000390704 (4:88438595 G>T), RS1000395146 (4:88394838 C>T), RS1000395721 (4:88386283 G>T), RS1000461491 (4:88422966 G>A), RS1000486776 (4:88426345 T>A), RS1000521118 (4:88400023 A>G)

Disease associations

OMIM: gene MIM:609249 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001639_19	Metabolite levels	1.000000e-10
GCST005956_59	Waist-to-hip ratio adjusted for BMI	5.000000e-08
GCST005957_14	Waist-to-hip ratio adjusted for BMI (age <50)	2.000000e-06
GCST005962_35	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-08
GCST008153_54	Lean body mass	9.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004995	lean body mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	7
Air Pollutants	decreases expression, increases abundance	3
Smoke	decreases expression, increases abundance, decreases reaction	3
entinostat	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Triclosan	affects cotreatment, increases expression	2
Cyclosporine	decreases expression, increases expression	2
sotorasib	affects cotreatment, increases expression	1
TL8-506	affects cotreatment, increases expression	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Decitabine	decreases expression, decreases reaction	1
Sunitinib	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_B1FJ	Abcam A-549 HERC6 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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