RNASEK

Summary

RNASEK (ribonuclease K, HGNC:33911) is a protein-coding gene on chromosome 17p13.1, encoding Ribonuclease kappa (Q6P5S7). Endoribonuclease which preferentially cleaves ApU and ApG phosphodiester bonds. It is a selective cancer dependency (DepMap: 53.5% of cell lines).

Enables RNA endonuclease activity. Involved in endosomal lumen acidification; proton transmembrane transport; and receptor-mediated endocytosis of virus by host cell. Located in membrane.

Source: NCBI Gene 440400 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 21 total
• Cancer dependency (DepMap): dependent in 53.5% of screened cell lines
• MANE Select transcript: NM_001004333

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33911
Approved symbol	RNASEK
Name	ribonuclease K
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC71993
Ensembl gene	ENSG00000219200
Ensembl biotype	protein_coding
OMIM	617098
Entrez	440400

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000546395, ENST00000548577, ENST00000549393, ENST00000552039, ENST00000552176, ENST00000552321, ENST00000552842, ENST00000570898, ENST00000575822, ENST00000593646

RefSeq mRNA: 1 — MANE Select: NM_001004333 NM_001004333

CCDS: CCDS45594

Canonical transcript exons

ENST00000593646 — 3 exons

Exon	Start	End
ENSE00003106463	7012624	7012761
ENSE00003568337	7014145	7014532
ENSE00003742691	7013666	7013742

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3777 / max 146.2397, expressed in 1659 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159082	509.0462	1828
159079	4.6721	1505
159078	2.1635	1168
159081	1.2124	546
159080	0.9054	474
159084	0.5878	225

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.58	gold quality
pituitary gland	UBERON:0000007	99.57	gold quality
right adrenal gland	UBERON:0001233	99.57	gold quality
left adrenal gland	UBERON:0001234	99.53	gold quality
adenohypophysis	UBERON:0002196	99.53	gold quality
left adrenal gland cortex	UBERON:0035825	99.53	gold quality
hypothalamus	UBERON:0001898	99.42	gold quality
granulocyte	CL:0000094	99.40	gold quality
metanephros cortex	UBERON:0010533	99.38	gold quality
monocyte	CL:0000576	99.36	gold quality
leukocyte	CL:0000738	99.36	gold quality
prefrontal cortex	UBERON:0000451	99.31	gold quality
right frontal lobe	UBERON:0002810	99.31	gold quality
nucleus accumbens	UBERON:0001882	99.30	gold quality
superior frontal gyrus	UBERON:0002661	99.29	gold quality
cortex of kidney	UBERON:0001225	99.28	gold quality
putamen	UBERON:0001874	99.28	gold quality
spleen	UBERON:0002106	99.28	gold quality
anterior cingulate cortex	UBERON:0009835	99.28	gold quality
right lung	UBERON:0002167	99.26	gold quality
frontal cortex	UBERON:0001870	99.25	gold quality
caudate nucleus	UBERON:0001873	99.24	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.24	gold quality
substantia nigra	UBERON:0002038	99.23	gold quality
amygdala	UBERON:0001876	99.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.22	gold quality
cerebral cortex	UBERON:0000956	99.21	gold quality
primary visual cortex	UBERON:0002436	99.21	gold quality
temporal lobe	UBERON:0001871	99.20	gold quality
Ammon’s horn	UBERON:0001954	99.20	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	1691.05
E-CURD-122	yes	46.84
E-GEOD-81547	yes	25.55
E-MTAB-9221	yes	19.29
E-ANND-3	yes	13.03
E-MTAB-10042	yes	10.32
E-GEOD-81608	no	777.40
E-MTAB-7037	no	642.39
E-GEOD-83139	no	627.70
E-HCAD-31	no	29.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting RNASEK, 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-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-4294	97.86	65.72	1110

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 53.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• Based on sequence alignment and substrate specificity data, as well as the resistance of the protein to the placental ribonuclease inhibitor, the human RNase kappa may be a novel endoribonuclease distinct from other known ribonucleases. (PMID:17881363)
• Data suggest that the Cys6-Cys69 disulfide bond is likely to exist in all RNase kappa family members, including human. (PMID:22324914)
• RNASEK closely associates with the V-ATPase and is required for its function; its loss prevents the early events of endocytosis and the replication of multiple pathogenic viruses. (PMID:26212330)
• Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with RNASEK gene expression, suggesting that RNASEK expression may mediate the effect of genotype on diabetes. (PMID:26487785)
• Low Rnase K expression is associated with prostate cancer. (PMID:30054827)
• Identification of novel alternative transcripts of the human Ribonuclease kappa (RNASEK) gene using 3’ RACE and high-throughput sequencing approaches. (PMID:31200028)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnaseka	ENSDARG00000069461
danio_rerio	rnasekb	ENSDARG00000104458
mus_musculus	Rnasek	ENSMUSG00000093989
rattus_norvegicus	Rnasek	ENSRNOG00000076162

Protein

Protein identifiers

Ribonuclease kappa — Q6P5S7 (reviewed: Q6P5S7)

Alternative names: V-type proton ATPase subunit f

All UniProt accessions (7): Q6P5S7, A0A087WSZ8, A0A0C4DH85, A0A0C4DH89, F8W1G5, H0YIM4, H0YIU3

UniProt curated annotations — full annotation on UniProt →

Function. Endoribonuclease which preferentially cleaves ApU and ApG phosphodiester bonds. Hydrolyzes UpU bonds at a lower rate. Regulates the activity of vacuolar (H+)-ATPase (V-ATPase) which is responsible for acidifying and maintaining the pH of intracellular compartments. Required at an early stage of receptor-mediated endocytosis. (Microbial infection) Required at an early stage of both clathrin-mediated and clathrin-independent endocytic uptake of a diverse set of viruses, including dengue, West Nile, Sindbis, Rift Valley Fever, influenza, and human rhinoviruses.

Subunit / interactions. Interacts with the proton translocation complex V0 of the V-ATPase. Interacts with ATP6AP1.

Subcellular location. Endomembrane system. Cytoplasmic vesicle. Clathrin-coated vesicle membrane.

Tissue specificity. Widely expressed.

Similarity. Belongs to the RNase K family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6P5S7-1	1	yes
Q6P5S7-2	2

RefSeq proteins (1): NP_001004333* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026770	RNase_K	Family
IPR056552

Pfam: PF23489

UniProt features (9 total): helix 3, transmembrane region 2, chain 1, splice variant 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6WLW	ELECTRON MICROSCOPY	3
9DET	ELECTRON MICROSCOPY	3
6WM2	ELECTRON MICROSCOPY	3.1
6WM3	ELECTRON MICROSCOPY	3.4
9CF8	ELECTRON MICROSCOPY	3.46
9CFC	ELECTRON MICROSCOPY	3.47
6WM4	ELECTRON MICROSCOPY	3.6
7U4T	ELECTRON MICROSCOPY	3.6
7UNF	ELECTRON MICROSCOPY	4.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P5S7-F1	66.09	0.00

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9918485	Dengue Virus Attachment and Entry

MSigDB gene sets: 137 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOMF_NUCLEASE_ACTIVITY, GOBP_VESICLE_ORGANIZATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOMF_RNA_ENDONUCLEASE_ACTIVITY, RAMALHO_STEMNESS_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOCC_COATED_VESICLE, GOBP_VACUOLAR_ACIDIFICATION, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_HOST

GO Biological Process (11): receptor-mediated endocytosis (GO:0006898), vacuolar acidification (GO:0007035), lysosomal lumen acidification (GO:0007042), receptor-mediated endocytosis of virus by host cell (GO:0019065), endosomal lumen acidification (GO:0048388), intracellular pH reduction (GO:0051452), Golgi lumen acidification (GO:0061795), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811), endocytosis (GO:0006897), nucleic acid metabolic process (GO:0090304)

GO Molecular Function (5): RNA endonuclease activity (GO:0004521), hydrolase activity (GO:0016787), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), vacuolar proton-transporting V-type ATPase, V0 domain (GO:0000220), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), clathrin-coated vesicle membrane (GO:0030665), proton-transporting V-type ATPase complex (GO:0033176), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular pH reduction	3
bounding membrane of organelle	2
cellular anatomical structure	2
endocytosis	1
vacuolar acidification	1
receptor-mediated endocytosis	1
symbiont entry into host cell	1
endocytosis involved in viral entry into host cell	1
endosome organization	1
regulation of intracellular pH	1
monoatomic cation transmembrane transport	1
transport	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
nucleobase-containing compound metabolic process	1
macromolecule metabolic process	1
endonuclease activity	1
RNA nuclease activity	1
catalytic activity	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
binding	1
Golgi apparatus	1
vacuolar membrane	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V0 domain	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
clathrin-coated vesicle	1
coated vesicle membrane	1
proton-transporting two-sector ATPase complex	1
cation-transporting ATPase complex	1
ATPase complex	1
vacuole	1

Protein interactions and networks

STRING

398 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASEK	ATP6AP1	Q15904	816
RNASEK	ATP6AP2	O75787	543
RNASEK	PNPT1	Q8TCS8	476
RNASEK	ELP5	Q8TE02	472
RNASEK	ASGR2	P07307	460
RNASEK	LY6E	Q16553	443
RNASEK	MEAK7	Q6P9B6	440
RNASEK	TRIQK	Q629K1	433
RNASEK	VMA22	Q96NT0	410
RNASEK	ALOXE3	Q9BYJ1	398
RNASEK	WDR7	Q9Y4E6	379
RNASEK	SLC16A11	Q8NCK7	359
RNASEK	RTL8B	Q17RB0	352
RNASEK	KRI1	Q8N9T8	332
RNASEK	TBC1D20	Q96BZ9	331

IntAct

74 interactions, top by confidence:

A	B	Type	Score
BNIP3	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
FXYD6	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
SERP2	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
RTP2	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
NINJ2	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
STX8	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	ATP13A1	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	ARV1	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	NINJ2	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
SMAGP	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	VTI1B	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	TMEM60	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	ZDHHC21	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	TREX1	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	TMEM203	psi-mi:“MI:0915”(physical association)	0.560
SERF1A	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	FXYD6	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	SERP2	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	GIMAP5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (29): RNASEK (Affinity Capture-RNA), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid), RNASEK (Two-hybrid)

ESM2 similar proteins: D3Z291, D3Z7H4, D3ZK93, F6V1J6, O75204, P51810, P51811, P70259, P82352, P97260, P97799, Q08CE6, Q08DE1, Q0IIE5, Q12770, Q14714, Q17QQ5, Q2T9K0, Q3ZCD2, Q494T4, Q498W5, Q49LS5, Q49LS8, Q4V922, Q504G0, Q5MNU5, Q5R7K2, Q5SNT2, Q5T4F4, Q5XGU1, Q62147, Q6P5F7, Q6P5S7, Q6UXU4, Q7RTS5, Q80UF9, Q80ZU9, Q8BGP5, Q8IZ57, Q8NFM7

Diamond homologs: A2VDC7, Q0P442, Q0P467, Q3ZC23, Q566G2, Q6P5S7, Q7Z0Q2, Q8K3C0, Q8MSF5, Q9NDV2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RNASEK	“form complex”	V-ATPase	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1107 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7013660:TTCCA:T	acceptor_loss	1.0000
17:7013661:TCCAG:T	acceptor_loss	1.0000
17:7013662:CCAG:C	acceptor_loss	1.0000
17:7013663:CA:C	acceptor_loss	1.0000
17:7013664:A:AG	acceptor_gain	1.0000
17:7013665:G:A	acceptor_loss	1.0000
17:7013665:G:GG	acceptor_gain	1.0000
17:7013665:GATA:G	acceptor_gain	1.0000
17:7013738:TTTGA:T	donor_gain	1.0000
17:7013739:TTGA:T	donor_gain	1.0000
17:7013740:TGA:T	donor_gain	1.0000
17:7013740:TGAGT:T	donor_loss	1.0000
17:7013741:GA:G	donor_gain	1.0000
17:7013741:GAG:G	donor_gain	1.0000
17:7013742:AG:A	donor_loss	1.0000
17:7013743:G:GG	donor_gain	1.0000
17:7013743:GTAA:G	donor_loss	1.0000
17:7013744:T:G	donor_loss	1.0000
17:7014269:G:GT	donor_gain	1.0000
17:7012747:G:GT	donor_gain	0.9900
17:7012747:G:T	donor_gain	0.9900
17:7012758:GTTG:G	donor_gain	0.9900
17:7013419:G:GT	donor_gain	0.9900
17:7013439:G:GT	donor_gain	0.9900
17:7013441:A:T	donor_gain	0.9900
17:7013536:G:GG	donor_gain	0.9900
17:7013651:ATTCC:A	donor_gain	0.9900
17:7013665:GA:G	acceptor_gain	0.9900
17:7013665:GAT:G	acceptor_gain	0.9900
17:7013665:GATAA:G	acceptor_gain	0.9900

AlphaMissense

645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:7012744:T:A	W60R	1.000
17:7012744:T:C	W60R	1.000
17:7013676:G:A	G69E	1.000
17:7012727:G:A	G54D	0.999
17:7012738:A:C	S58R	0.999
17:7012740:C:A	S58R	0.999
17:7012740:C:G	S58R	0.999
17:7012747:G:A	G61R	0.999
17:7012747:G:C	G61R	0.999
17:7012748:G:A	G61E	0.999
17:7012758:G:A	M64I	0.999
17:7012758:G:C	M64I	0.999
17:7012758:G:T	M64I	0.999
17:7012760:T:C	L65S	0.999
17:7013673:T:A	L68H	0.999
17:7013675:G:A	G69R	0.999
17:7013675:G:C	G69R	0.999
17:7013679:T:A	I70K	0.999
17:7013684:T:C	F72L	0.999
17:7013686:C:A	F72L	0.999
17:7013686:C:G	F72L	0.999
17:7013706:T:C	L79S	0.999
17:7013714:G:C	D82H	0.999
17:7014194:T:C	C108R	0.999
17:7014195:G:A	C108Y	0.999
17:7014196:T:G	C108W	0.999
17:7014204:C:A	A111D	0.999
17:7014227:G:A	G119R	0.999
17:7014227:G:C	G119R	0.999
17:7014228:G:A	G119E	0.999

dbSNP variants (sampled 300 via entrez): RS1000296550 (17:7012914 G>A,C), RS1001415260 (17:7012095 G>T), RS1001518276 (17:7011476 T>C), RS1001930551 (17:7013152 G>A), RS1003843299 (17:7013170 G>A), RS1004861897 (17:7012186 TCTTA>T), RS1005748390 (17:7011005 A>G), RS1006086866 (17:7012613 G>A,C,T), RS1007762344 (17:7014018 A>C,G,T), RS1007981173 (17:7014803 C>A,G,T), RS1008095763 (17:7014995 G>A), RS1009085041 (17:7012871 C>G,T), RS1010093190 (17:7011712 G>C,T), RS1010102032 (17:7011995 G>A), RS1010263281 (17:7012324 T>C)

Disease associations

OMIM: gene MIM:617098 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
aristolochic acid I	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases 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	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Doxorubicin	increases expression	1
Ozone	affects expression, increases abundance	1
Dronabinol	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TJ17	HAP1 RNASEK (-) 1	Cancer cell line	Male
CVCL_TJ18	HAP1 RNASEK (-) 2	Cancer cell line	Male
CVCL_TJ19	HAP1 RNASEK (-) 3	Cancer cell line	Male
CVCL_TJ20	HAP1 RNASEK (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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