KLHDC10

Summary

KLHDC10 (kelch domain containing 10, HGNC:22194) is a protein-coding gene on chromosome 7q32.2, encoding Kelch domain-containing protein 10 (Q6PID8). Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C-terminus of target proteins, leading to their ubiquitination and degradation.

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in rescue of stalled ribosome and ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nucleoplasm. Is active in Cul2-RING ubiquitin ligase complex and cytoplasm.

Source: NCBI Gene 23008 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 37 total
• MANE Select transcript: NM_014997

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22194
Approved symbol	KLHDC10
Name	kelch domain containing 10
Location	7q32.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0265, slim
Ensembl gene	ENSG00000128607
Ensembl biotype	protein_coding
OMIM	615152
Entrez	23008

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000335420, ENST00000463413, ENST00000468226, ENST00000495724, ENST00000851918

RefSeq mRNA: 1 — MANE Select: NM_014997 NM_014997

CCDS: CCDS5815

Canonical transcript exons

ENST00000335420 — 10 exons

Exon	Start	End
ENSE00000882303	130129437	130129576
ENSE00000882304	130127404	130127451
ENSE00000882305	130125865	130125931
ENSE00000882306	130124451	130124535
ENSE00000882307	130122054	130122202
ENSE00000882308	130120749	130120903
ENSE00001348790	130130537	130135705
ENSE00001368008	130070534	130070809
ENSE00003542856	130116445	130116666
ENSE00003578403	130096921	130097007

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.0760 / max 126.1255, expressed in 1809 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81050	16.0760	1809

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.18	gold quality
pancreatic ductal cell	CL:0002079	99.00	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.76	gold quality
choroid plexus epithelium	UBERON:0003911	98.43	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.35	gold quality
middle temporal gyrus	UBERON:0002771	97.80	gold quality
sperm	CL:0000019	97.70	gold quality
inferior olivary complex	UBERON:0002127	96.87	gold quality
visceral pleura	UBERON:0002401	96.85	gold quality
cervix squamous epithelium	UBERON:0006922	96.80	gold quality
substantia nigra pars compacta	UBERON:0001965	96.72	gold quality
renal glomerulus	UBERON:0000074	96.64	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.63	gold quality
metanephric glomerulus	UBERON:0004736	96.36	gold quality
parietal pleura	UBERON:0002400	96.31	gold quality
male germ cell	CL:0000015	96.28	gold quality
gingival epithelium	UBERON:0001949	96.20	gold quality
pleura	UBERON:0000977	96.19	gold quality
tibia	UBERON:0000979	95.95	gold quality
nephron tubule	UBERON:0001231	95.78	gold quality
superior vestibular nucleus	UBERON:0007227	95.59	gold quality
entorhinal cortex	UBERON:0002728	95.58	gold quality
skin of hip	UBERON:0001554	95.57	gold quality
tongue squamous epithelium	UBERON:0006919	95.40	gold quality
kidney epithelium	UBERON:0004819	95.37	gold quality
medulla oblongata	UBERON:0001896	95.29	gold quality
cranial nerve II	UBERON:0000941	95.12	gold quality
squamous epithelium	UBERON:0006914	95.06	gold quality
gingiva	UBERON:0001828	94.93	gold quality
pons	UBERON:0000988	94.85	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.59
E-MTAB-6386	no	105.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

205 targeting KLHDC10, 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-5692A	100.00	74.40	6850
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 2)

• Suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5. (PMID:23102700)
• Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10. (PMID:37676773)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhdc10	ENSDARG00000007764
mus_musculus	Klhdc10	ENSMUSG00000029775
rattus_norvegicus	Klhdc10	ENSRNOG00000010267
caenorhabditis_elegans		WBGENE00013461

Paralogs (10): FBXO42 (ENSG00000037637), LZTR1 (ENSG00000099949), KLHDC4 (ENSG00000104731), HCFC2 (ENSG00000111727), KLHDC3 (ENSG00000124702), RABEPK (ENSG00000136933), KLHDC9 (ENSG00000162755), KLHDC2 (ENSG00000165516), HCFC1 (ENSG00000172534), KLHDC1 (ENSG00000197776)

Protein

Protein identifiers

Kelch domain-containing protein 10 — Q6PID8 (reviewed: Q6PID8)

All UniProt accessions (3): Q6PID8, C9JRT7, C9JRX2

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C-terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(KLHDC10) complex specifically recognizes proteins with a proline-glycine (Pro-Gly) or an alanine tail (CAT tail) at the C-terminus, leading to their ubiquitination and degradation. The CRL2(KLHDC10) complex is involved in the ribosome-associated quality control (RQC) pathway, which mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes: CRL2(KLHDC10) acts downstream of NEMF and recognizes CAT tails associated with stalled nascent chains, leading to their ubiquitination and degradation. Participates in the oxidative stress-induced cell death through MAP3K5 activation. Inhibits PPP5C phosphatase activity on MAP3K5. Acts as a regulator of necroptosis.

Subunit / interactions. Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC10. Interacts (via the 6 Kelch repeats) with PPP5C.

Subcellular location. Nucleus. Cytoplasm.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the KLHDC10 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6PID8-1	1	yes
Q6PID8-2	2

RefSeq proteins (1): NP_055812* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006652	Kelch_1	Repeat
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR052125	KLHDC10	Family

Pfam: PF01344, PF24681

UniProt features (62 total): strand 30, turn 9, repeat 6, sequence variant 5, helix 5, region of interest 2, chain 1, modified residue 1, splice variant 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9D8P	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PID8-F1	85.43	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.

Post-translational modifications (1): 13

Mutagenesis-validated functional residues (1):

Position	Phenotype
409	loss of interaction with cul2. no effect on map3k5 activation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9954709	Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

MSigDB gene sets: 219 (showing top): MORF_MSH3, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, MORF_BRCA1, MORF_ATRX, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, SCIBETTA_KDM5B_TARGETS_UP, MODULE_453, AAAYRNCTG_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, MODULE_503, ATGTTAA_MIR302C, GOBP_TRANSLATION, MODULE_195

GO Biological Process (4): protein ubiquitination (GO:0016567), positive regulation of stress-activated MAPK cascade (GO:0032874), rescue of stalled cytosolic ribosome (GO:0072344), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Cul2-RING ubiquitin ligase complex (GO:0031462), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein modification by small protein conjugation	1
regulation of stress-activated MAPK cascade	1
positive regulation of MAPK cascade	1
stress-activated MAPK cascade	1
positive regulation of stress-activated protein kinase signaling cascade	1
cytoplasmic translational elongation	1
ribosome disassembly	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1070 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHDC10	PLEKHD1	A6NEE1	569
KLHDC10	UBE2H	P37286	525
KLHDC10	MKLN1	Q9UL63	512
KLHDC10	NRK	Q7Z2Y5	495
KLHDC10	DCAF10	Q5QP82	491
KLHDC10	KLHDC7A	Q5VTJ3	486
KLHDC10	NUDT12	Q9BQG2	458
KLHDC10	TSGA13	Q96PP4	451
KLHDC10	ZC3HC1	Q86WB0	447
KLHDC10	ATOSB	Q7L5A3	409
KLHDC10	TMEM209	Q96SK2	400
KLHDC10	KBTBD13	C9JR72	399
KLHDC10	ZSWIM5	Q9P217	399
KLHDC10	BSDC1	Q9NW68	391
KLHDC10	CEP41	Q9BYV8	370
KLHDC10	PRRT4	C9JH25	370

IntAct

56 interactions, top by confidence:

A	B	Type	Score
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
PIK3CB	PIK3R1	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	KLHDC10	psi-mi:“MI:0403”(colocalization)	0.680
KLHDC10	CUL2	psi-mi:“MI:0914”(association)	0.640
PRKD1	PRKD3	psi-mi:“MI:0914”(association)	0.640
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
NUDCD3	KLHDC10	psi-mi:“MI:0915”(physical association)	0.560
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
GLMN	MGST3	psi-mi:“MI:0914”(association)	0.530
PYCR3	RPL23	psi-mi:“MI:0914”(association)	0.530
CUL2	RNF187	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
KLHDC10	CDC37	psi-mi:“MI:0915”(physical association)	0.400
Smc1a	PDS5B	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
NEDD8	DDX3X	psi-mi:“MI:0914”(association)	0.350
RIN3		psi-mi:“MI:0914”(association)	0.350

BioGRID (66): KLHDC10 (Affinity Capture-RNA), KLHDC10 (Affinity Capture-RNA), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), KLHDC10 (Affinity Capture-RNA), KLHDC10 (Affinity Capture-MS)

ESM2 similar proteins: A2AAX3, A2AGL3, B0LPN4, D3ZA50, D4ABP9, E9Q401, G3X9X1, P30957, Q0IIC2, Q15413, Q28DE7, Q3KRE6, Q3UGM2, Q4G5Y1, Q4R3J7, Q58CV6, Q5E9A7, Q5F361, Q5M9G8, Q5R7H5, Q5RDA9, Q5RDY3, Q5U3Y0, Q5U580, Q5ZJU2, Q6AYI2, Q6P3S6, Q6PAR0, Q6PDJ6, Q6PID8, Q6ZN16, Q7Z6M1, Q80YG3, Q8BGZ3, Q8BM85, Q8IY47, Q8N7A1, Q8TEA7, Q8TEB1, Q8VDD9

Diamond homologs: A1ZB86, Q0IIC2, Q28DE7, Q5U3Y0, Q5U580, Q6PAR0, Q6PID8, Q86L99, Q8IID4, Q921I2, Q5R8W1, Q5VV63, Q6A051, A2AB59, A8JAM0, B0S6J3, B2RTY4, E7EZG2, E7F3F0, O14248, O43295, O75044, P38853, P46941, P50090, P80197, P81128, P83509, P85298, P87061, P98171, Q07960, Q10164, Q10AZ7, Q12128, Q2QM47, Q39610, Q4V8F4, Q54E35, Q54F80

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2172 predictions. Top by Δscore:

Variant	Effect	Δscore
7:130116662:GTCAC:G	donor_gain	1.0000
7:130116667:G:GG	donor_gain	1.0000
7:130120747:A:AG	acceptor_gain	1.0000
7:130120748:G:GG	acceptor_gain	1.0000
7:130120748:GTT:G	acceptor_gain	1.0000
7:130122198:GAGAG:G	donor_gain	1.0000
7:130122200:GAG:G	donor_gain	1.0000
7:130122203:G:C	donor_loss	1.0000
7:130122204:T:A	donor_loss	1.0000
7:130124449:A:AG	acceptor_gain	1.0000
7:130124450:G:GG	acceptor_gain	1.0000
7:130124532:CAAG:C	donor_loss	1.0000
7:130124533:AAG:A	donor_loss	1.0000
7:130124535:GGTAT:G	donor_loss	1.0000
7:130124536:G:A	donor_loss	1.0000
7:130124537:T:G	donor_loss	1.0000
7:130125862:A:AG	acceptor_gain	1.0000
7:130125863:A:G	acceptor_gain	1.0000
7:130125928:A:AG	donor_gain	1.0000
7:130127399:GGCA:G	acceptor_loss	1.0000
7:130127401:CA:C	acceptor_loss	1.0000
7:130127402:AGG:A	acceptor_loss	1.0000
7:130127403:G:GT	acceptor_loss	1.0000
7:130127448:AATG:A	donor_gain	1.0000
7:130127450:TGG:T	donor_loss	1.0000
7:130127452:G:GG	donor_gain	1.0000
7:130127452:GT:G	donor_loss	1.0000
7:130127453:T:TC	donor_loss	1.0000
7:130129431:TCATA:T	acceptor_loss	1.0000
7:130129435:A:AG	acceptor_gain	1.0000

AlphaMissense

2877 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:130116471:G:A	G94R	1.000
7:130116471:G:C	G94R	1.000
7:130116472:G:A	G94E	1.000
7:130116472:G:T	G94V	1.000
7:130116502:T:C	L104P	1.000
7:130116513:G:A	G108R	1.000
7:130116513:G:C	G108R	1.000
7:130116514:G:A	G108E	1.000
7:130116514:G:T	G108V	1.000
7:130116516:G:C	G109R	1.000
7:130116517:G:A	G109D	1.000
7:130116517:G:T	G109V	1.000
7:130116583:T:C	L131P	1.000
7:130116612:T:A	W141R	1.000
7:130116612:T:C	W141R	1.000
7:130116657:T:C	S156P	1.000
7:130120781:G:A	G170R	1.000
7:130120781:G:C	G170R	1.000
7:130120782:G:A	G170E	1.000
7:130120782:G:T	G170V	1.000
7:130120784:G:C	G171R	1.000
7:130120784:G:T	G171C	1.000
7:130120785:G:A	G171D	1.000
7:130120785:G:T	G171V	1.000
7:130120799:T:A	F176I	1.000
7:130120799:T:C	F176L	1.000
7:130120800:T:G	F176C	1.000
7:130120801:T:A	F176L	1.000
7:130120801:T:G	F176L	1.000
7:130120802:G:A	G177R	1.000

dbSNP variants (sampled 300 via entrez): RS1000062522 (7:130085081 C>T), RS1000158491 (7:130103695 C>T), RS1000180528 (7:130112246 G>T), RS1000199041 (7:130090906 C>A,T), RS1000241851 (7:130091511 A>G), RS1000580056 (7:130100406 G>C), RS1000613414 (7:130091232 A>G), RS1000690971 (7:130086043 G>T), RS1000734788 (7:130097528 A>G), RS1000805294 (7:130131839 G>A), RS1000853755 (7:130079139 C>A,T), RS1000869257 (7:130072026 A>G), RS1000896800 (7:130092491 T>C), RS1001005715 (7:130118349 T>G), RS1001031704 (7:130103949 A>C,T)

Disease associations

OMIM: gene MIM:615152 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_2076	Metabolite levels	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010372	phosphatidylcholine 32:0 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
cobaltous chloride	increases expression	2
Lead	affects expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
torcetrapib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Coumestrol	decreases expression	1
Endosulfan	decreases expression	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Plant Oils	increases expression	1
Selenium	decreases expression	1
Testosterone	decreases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1
Vitamin E	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2AD	HAP1 KLHDC10 (-) 1	Cancer cell line	Male
CVCL_E2AE	HAP1 KLHDC10 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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