KLHL11

Summary

KLHL11 (kelch like family member 11, HGNC:19008) is a protein-coding gene on chromosome 17q21.2, encoding Kelch-like protein 11 (Q9NVR0). Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, leading most often to their proteasomal degradation. It is a selective cancer dependency (DepMap: 10.4% of cell lines).

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm.

Source: NCBI Gene 55175 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 50 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.4% of screened cell lines
• MANE Select transcript: NM_018143

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19008
Approved symbol	KLHL11
Name	kelch like family member 11
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10572
Ensembl gene	ENSG00000178502
Ensembl biotype	protein_coding
OMIM	619078
Entrez	55175

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000319121

RefSeq mRNA: 1 — MANE Select: NM_018143 NM_018143

CCDS: CCDS11411

Canonical transcript exons

ENST00000319121 — 2 exons

Exon	Start	End
ENSE00001291142	41864826	41865423
ENSE00002549532	41848518	41855321

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 89.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0005 / max 138.0397, expressed in 1775 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166054	6.7119	1648
166053	5.0428	1639
166055	1.2458	733

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	89.44	gold quality
male germ cell	CL:0000015	86.99	gold quality
secondary oocyte	CL:0000655	82.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.72	gold quality
calcaneal tendon	UBERON:0003701	80.27	gold quality
tendon	UBERON:0000043	77.75	gold quality
islet of Langerhans	UBERON:0000006	76.62	gold quality
adrenal tissue	UBERON:0018303	76.60	gold quality
cortical plate	UBERON:0005343	75.72	gold quality
stromal cell of endometrium	CL:0002255	75.07	gold quality
medial globus pallidus	UBERON:0002477	74.53	gold quality
tendon of biceps brachii	UBERON:0008188	73.46	gold quality
ventricular zone	UBERON:0003053	72.89	gold quality
ganglionic eminence	UBERON:0004023	72.80	gold quality
monocyte	CL:0000576	71.55	gold quality
mononuclear cell	CL:0000842	71.46	gold quality
leukocyte	CL:0000738	71.24	gold quality
prefrontal cortex	UBERON:0000451	69.57	gold quality
gastrocnemius	UBERON:0001388	68.87	gold quality
muscle of leg	UBERON:0001383	68.42	gold quality
testis	UBERON:0000473	67.71	gold quality
globus pallidus	UBERON:0001875	67.40	gold quality
left testis	UBERON:0004533	67.02	gold quality
right testis	UBERON:0004534	66.98	gold quality
colonic epithelium	UBERON:0000397	66.17	silver quality
pancreas	UBERON:0001264	65.03	gold quality
smooth muscle tissue	UBERON:0001135	64.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	63.99	gold quality
corpus callosum	UBERON:0002336	63.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	63.83	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6058	no	717.22
E-ANND-3	no	4.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

258 targeting KLHL11, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548P	99.98	72.25	3784
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-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• analysis of crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3 (PMID:23349464)
• Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis. (PMID:32744608)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl11	ENSDARG00000045130
mus_musculus	Klhl11	ENSMUSG00000048732
rattus_norvegicus	Klhl11	ENSRNOG00000016921
drosophila_melanogaster	BTBD9	FBGN0030228
drosophila_melanogaster	CG17068	FBGN0031098
drosophila_melanogaster	lute	FBGN0262871
caenorhabditis_elegans		WBGENE00015463

Paralogs (11): BTBD1 (ENSG00000064726), ABTB1 (ENSG00000114626), SPOP (ENSG00000121067), KBTBD4 (ENSG00000123444), BTBD3 (ENSG00000132640), BTBD2 (ENSG00000133243), SPOPL (ENSG00000144228), ABTB3 (ENSG00000151136), ABTB2 (ENSG00000166016), BTBD9 (ENSG00000183826), BTBD6 (ENSG00000184887)

Protein

Protein identifiers

Kelch-like protein 11 — Q9NVR0 (reviewed: Q9NVR0)

All UniProt accessions (1): Q9NVR0

UniProt curated annotations — full annotation on UniProt →

Function. Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, leading most often to their proteasomal degradation.

Subunit / interactions. Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex. Homodimer. Interacts with CUL3.

RefSeq proteins (1): NP_060613* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily

Pfam: PF00651, PF07707, PF13964

UniProt features (41 total): helix 19, strand 6, turn 5, repeat 5, domain 2, signal peptide 1, chain 1, modified residue 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3I3N	X-RAY DIFFRACTION	2.6
4AP2	X-RAY DIFFRACTION	2.8
4APF	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NVR0-F1	82.68	0.53

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): 465

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 135 (showing top): GCM_GSPT1, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, OCT1_06, GCM_NF2, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX, GOCC_CUL3_RING_UBIQUITIN_LIGASE_COMPLEX, WGTTNNNNNAAA_UNKNOWN, E2F1_Q3_01

GO Biological Process (1): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

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

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), Cul3-RING ubiquitin ligase complex (GO:0031463)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

550 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL11	CUL3	Q13618	794
KLHL11	IGLON5	A6NGN9	587
KLHL11	LUZP4	Q9P127	581
KLHL11	SEPTIN5	Q99719	577
KLHL11	DPYSL5	Q9BPU6	571
KLHL11	PNMA2	Q9UL42	506
KLHL11	PDE10A	Q9Y233	492
KLHL11	FBXL15	Q9H469	446
KLHL11	AMPH	P49418	423
KLHL11	LGI1	O95970	417
KLHL11	NCDN	Q9UBB6	416
KLHL11	BIN1	O00499	411
KLHL11	KLHDC2	Q9Y2U9	409
KLHL11	RBX1	P62877	407
KLHL11	EOLA2	Q96DE9	400

IntAct

32 interactions, top by confidence:

A	B	Type	Score
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
CUL3	ENC1	psi-mi:“MI:0914”(association)	0.640
KLHL11	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
IHO1	KLHL11	psi-mi:“MI:0915”(physical association)	0.560
POU6F2	KLHL11	psi-mi:“MI:0915”(physical association)	0.560
CUL3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
CASQ2	PES1	psi-mi:“MI:0914”(association)	0.530
KIAA0930	ATG7	psi-mi:“MI:0914”(association)	0.530
KLHL11	NUDCD3	psi-mi:“MI:0915”(physical association)	0.400
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
TRIM35	LIMK2	psi-mi:“MI:0914”(association)	0.350
CUL3	KLHL2	psi-mi:“MI:0914”(association)	0.350
CASQ2	TSNARE1	psi-mi:“MI:0914”(association)	0.350
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.350
KIAA0930	FRYL	psi-mi:“MI:0914”(association)	0.350
C1QL4	SMC2	psi-mi:“MI:0914”(association)	0.350
KLHL11	PIPSL	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
C1QL4	SRC	psi-mi:“MI:0914”(association)	0.350
RBAK	CYP24A1	psi-mi:“MI:0914”(association)	0.350
KLHL11	PSMD12	psi-mi:“MI:0914”(association)	0.350
KLHL11	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
KLHL11	IHO1	psi-mi:“MI:0915”(physical association)	0.000
KLHL11	POU6F2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (97): KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-MS), KLHL11 (Affinity Capture-Western), KLHL11 (Affinity Capture-Western), KLHL11 (Co-localization), KLHL11 (PCA)

ESM2 similar proteins: A0A1B8YAB1, B1H285, B3DIV9, E9QIN8, E9QJ30, F1QEG2, O88879, Q08CL3, Q08CY1, Q0D2A9, Q13939, Q28068, Q3UQV5, Q3ZCT8, Q503R4, Q5F3N5, Q5R4S6, Q5R663, Q5RG82, Q5XHZ6, Q5XI58, Q5ZI33, Q69ZK5, Q6DFF7, Q6DFU2, Q6Q7X9, Q6V595, Q7ZVQ8, Q86V97, Q8BHI4, Q8BUL5, Q8BWA5, Q8CA72, Q8CDE2, Q8CE33, Q8IXQ5, Q8NAB2, Q8NFY9, Q8R179, Q8WVZ9

Diamond homologs: A0JMG1, A1YEX3, B0WWP2, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, B7U179, D3Z8N4, D4A2K4, E0CZ16, E7F6F9, F1LZF0, F1MBP6, O14682, O22286, O35709, O43791, O81432, O95198, P0DMR5, P0DMR6, P24278, P28575, P34568, P58544, P58545, Q08DK3, Q08DS0, Q0D2A9, Q0IHH9, Q0VCW1, Q16RL8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

144 predictions. Top by Δscore:

Variant	Effect	Δscore
17:41855322:C:CA	acceptor_loss	1.0000
17:41855322:C:CC	acceptor_gain	1.0000
17:41855317:GGAAC:G	acceptor_gain	0.9900
17:41855318:GAAC:G	acceptor_gain	0.9900
17:41855320:AC:A	acceptor_gain	0.9900
17:41855321:CC:C	acceptor_gain	0.9900
17:41855323:T:A	acceptor_loss	0.9900
17:41855329:C:CT	acceptor_gain	0.9900
17:41855330:A:T	acceptor_gain	0.9900
17:41860893:A:AC	donor_gain	0.9900
17:41860894:T:C	donor_gain	0.9900
17:41864822:CTACC:C	donor_loss	0.9900
17:41864823:TA:T	donor_loss	0.9900
17:41864825:C:CT	donor_loss	0.9900
17:41855319:AAC:A	acceptor_gain	0.9800
17:41859085:C:CA	donor_gain	0.9800
17:41864824:A:AC	donor_gain	0.9800
17:41864825:C:CC	donor_gain	0.9800
17:41855320:ACCT:A	acceptor_gain	0.9700
17:41864825:CCTGT:C	donor_gain	0.9700
17:41855319:AACCT:A	acceptor_gain	0.9600
17:41855321:CCT:C	acceptor_gain	0.9600
17:41855322:C:A	acceptor_gain	0.9600
17:41855322:C:T	acceptor_gain	0.9500
17:41855323:T:G	acceptor_gain	0.9500
17:41855318:GAACC:G	acceptor_gain	0.9200
17:41862906:A:AC	donor_gain	0.9200
17:41862907:C:CC	donor_gain	0.9200
17:41864838:TCCAG:T	donor_gain	0.9200
17:41864839:CCAGC:C	donor_gain	0.9200

AlphaMissense

4654 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:41853946:A:G	W641R	1.000
17:41853946:A:T	W641R	1.000
17:41854023:C:T	G615E	1.000
17:41854491:C:T	G459E	1.000
17:41854570:A:G	W433R	1.000
17:41854570:A:T	W433R	1.000
17:41854629:C:T	G413E	1.000
17:41854706:C:A	W387C	1.000
17:41854706:C:G	W387C	1.000
17:41854708:A:G	W387R	1.000
17:41854708:A:T	W387R	1.000
17:41854729:A:C	Y380D	1.000
17:41854773:C:T	G365E	1.000
17:41855050:A:G	W273R	1.000
17:41855050:A:T	W273R	1.000
17:41855233:C:G	A212P	1.000
17:41855280:A:G	L196P	1.000
17:41855291:A:C	C192W	1.000
17:41855292:C:T	C192Y	1.000
17:41864833:C:G	A180P	1.000
17:41864841:A:G	L177P	1.000
17:41864880:C:A	G164V	1.000
17:41864881:C:A	G164W	1.000
17:41865006:A:G	F122S	1.000
17:41865087:T:A	D95V	1.000
17:41865108:C:G	R88P	1.000
17:41853900:G:T	A656D	0.999
17:41853916:G:T	R651S	0.999
17:41853944:C:A	W641C	0.999
17:41853944:C:G	W641C	0.999

dbSNP variants (sampled 300 via entrez): RS1000043828 (17:41864776 T>C), RS1000049906 (17:41861591 C>G), RS1000142918 (17:41861373 C>T), RS1000251684 (17:41854632 G>A), RS1000512178 (17:41866479 A>G), RS1002161785 (17:41850060 C>A), RS1002190295 (17:41856734 T>A), RS1002384469 (17:41863300 C>A,T), RS1002764446 (17:41851928 A>T), RS1002948506 (17:41859429 G>A), RS1003146124 (17:41858110 G>A), RS1003468047 (17:41866435 G>A), RS1003850633 (17:41857424 T>G), RS1003962952 (17:41864194 C>A,G), RS1005040020 (17:41849975 T>C)

Disease associations

OMIM: gene MIM:619078 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST90002386_187	High light scatter reticulocyte percentage of red cells	9.000000e-35
GCST90002387_30	Immature fraction of reticulocytes	6.000000e-41
GCST90002405_328	Reticulocyte count	7.000000e-25
GCST90002406_461	Reticulocyte fraction of red cells	2.000000e-22

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196121 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Estradiol	increases expression	2
Tobacco Smoke Pollution	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
testosterone undecanoate	increases expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression	1
ferrous chloride	increases expression	1
resorcinol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, increases expression	1
Plant Oils	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Vanadates	decreases expression	1
Cyclosporine	increases expression	1
Palmitic Acid	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6094267	Binding	Binding affinity to KLHL11 (unknown origin) at 10 uM by thermal shift assay	Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors. — J Med Chem

Clinical trials (associated diseases)

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