EXOSC5

Summary

EXOSC5 (exosome component 5, HGNC:24662) is a protein-coding gene on chromosome 19q13.2, encoding Exosome complex component RRP46 (Q9NQT4). Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. It is a common-essential gene (DepMap: required in 92.3% of cancer cell lines).

Predicted to enable RNA binding activity. Involved in DNA deamination; RNA processing; and mRNA catabolic process. Acts upstream of or within defense response to virus. Located in cytosol; euchromatin; and nucleolus. Part of exosome (RNase complex).

Source: NCBI Gene 56915 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Gene–disease (curated): cerebellar ataxia, brain abnormalities, and cardiac conduction defects (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 76 total — 3 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 33 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 49
• Cancer dependency (DepMap): dependent in 92.3% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.14 (unconstrained)
• MANE Select transcript: NM_020158
• Interaction hub: 1,913 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24662
Approved symbol	EXOSC5
Name	exosome component 5
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	hRrp46p, Rrp46p, RRP46, RRP41B, MGC12901, p12B
Ensembl gene	ENSG00000077348
Ensembl biotype	protein_coding
OMIM	606492
Entrez	56915

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 17 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000221233

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 1, TSL 5: 1

ENST00000221233, ENST00000593523, ENST00000593771, ENST00000596905, ENST00000602129, ENST00000688768, ENST00000916935, ENST00000916936, ENST00000916937, ENST00000916938, ENST00000916939, ENST00000916940, ENST00000982797, ENST00001090449, ENST00001090450, ENST00001090452, ENST00001090458, ENST00001091994, ENST00001106697, ENST00001130566, ENST00001130567, ENST00001142194

RefSeq mRNA: 1 — MANE Select: NM_020158 NM_020158

CCDS: CCDS12580

Canonical transcript exons

ENST00000221233 — 6 exons

Exon	Start	End
ENSE00000550885	41391841	41391962
ENSE00000708419	41387514	41387603
ENSE00000708420	41389765	41389905
ENSE00000842445	41386374	41386725
ENSE00003213517	41397181	41397359
ENSE00003600642	41392867	41392980

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 92.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.6885 / max 150.3751, expressed in 1799 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, gastrocnemius, hindlimb stylopod muscle.

Genetic regulation across tissues (GTEx eQTL / sQTL)

EXOSC5 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 33 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 34 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	7.7e-42	-0.69	19:41411513:G:GC
Muscle Skeletal	eqtl	2.0e-28	-0.23	19:41380954:T:C
Heart Left Ventricle	eqtl	2.9e-22	-0.32	19:41408571:T:C
Brain Cerebellar Hemisphere	eqtl	3.3e-16	-0.37	19:41402966:G:A
Cells EBV-transformed lymphocytes	eqtl	1.7e-12	-0.48	19:41394904:C:T
Brain Cerebellum	eqtl	7.6e-10	-0.38	19:41386069:C:T
Brain Hippocampus	eqtl	1.4e-09	-0.24	19:41396406:C:T
Thyroid	eqtl	5.0e-09	-0.20	19:41422819:G:A
Pituitary	eqtl	5.3e-09	-0.34	19:41386069:C:T
Heart Atrial Appendage	eqtl	5.0e-08	-0.29	19:41425549:A:AGGCCAGGGCCGG
Artery Aorta	eqtl	3.5e-07	-0.22	19:41412253:C:T
Artery Tibial	eqtl	2.9e-06	-0.15	19:41380954:T:C
Esophagus Muscularis	eqtl	1.0e-05	-0.16	19:41403031:T:A
Pancreas	eqtl	1.2e-05	-0.16	19:41402966:G:A
Lung	eqtl	1.5e-05	-0.11	19:41408571:T:C
Prostate	eqtl	2.7e-04	-0.22	19:41403031:T:A
Brain Hypothalamus	eqtl	1.4e-03	-0.21	19:41380550:T:G
Esophagus Gastroesophageal Junction	eqtl	1.9e-03	-0.21	19:41425549:A:AGGCCAGGGCCGG
Brain Cortex	eqtl	2.4e-03	+0.29	19:41363040:T:TTCGAGA
Brain Spinal cord cervical c-1	eqtl	3.9e-03	-0.21	19:41386364:C:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
181058	24.6885	1799

Top tissues by expression

showing 100 of 267 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	92.71	gold quality
mononuclear cell	CL:0000842	92.26	gold quality
leukocyte	CL:0000738	91.72	gold quality
gastrocnemius	UBERON:0001388	91.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.55	gold quality
lower esophagus mucosa	UBERON:0035834	90.38	gold quality
muscle of leg	UBERON:0001383	90.14	gold quality
body of pancreas	UBERON:0001150	89.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.85	gold quality
prefrontal cortex	UBERON:0000451	88.77	gold quality
right adrenal gland	UBERON:0001233	88.13	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.13	gold quality
cortical plate	UBERON:0005343	88.12	gold quality
skin of abdomen	UBERON:0001416	87.86	gold quality
skin of leg	UBERON:0001511	87.83	gold quality
granulocyte	CL:0000094	87.68	gold quality
apex of heart	UBERON:0002098	87.47	gold quality
left adrenal gland	UBERON:0001234	87.35	gold quality
left adrenal gland cortex	UBERON:0035825	87.30	gold quality
esophagus mucosa	UBERON:0002469	87.26	gold quality
mucosa of transverse colon	UBERON:0004991	87.04	gold quality
right adrenal gland cortex	UBERON:0035827	87.01	gold quality
muscle organ	UBERON:0001630	86.63	gold quality
anterior cingulate cortex	UBERON:0009835	86.27	gold quality
cingulate cortex	UBERON:0003027	86.12	gold quality
right lobe of liver	UBERON:0001114	86.00	gold quality
nucleus accumbens	UBERON:0001882	85.93	gold quality
right frontal lobe	UBERON:0002810	85.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.83	gold quality
adrenal cortex	UBERON:0001235	85.82	gold quality
zone of skin	UBERON:0000014	85.80	gold quality
spinal cord	UBERON:0002240	85.72	gold quality
caudate nucleus	UBERON:0001873	85.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.20	gold quality
adrenal gland	UBERON:0002369	85.16	gold quality
putamen	UBERON:0001874	84.87	gold quality
esophagus	UBERON:0001043	84.84	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.74	gold quality
body of stomach	UBERON:0001161	84.73	gold quality
ganglionic eminence	UBERON:0004023	84.40	gold quality
right ovary	UBERON:0002118	84.37	gold quality
neocortex	UBERON:0001950	84.18	gold quality
heart left ventricle	UBERON:0002084	84.11	gold quality
frontal cortex	UBERON:0001870	83.98	gold quality
left ovary	UBERON:0002119	83.88	gold quality
right uterine tube	UBERON:0001302	83.73	gold quality
tibial nerve	UBERON:0001323	83.68	gold quality
cardiac ventricle	UBERON:0002082	83.54	gold quality
amygdala	UBERON:0001876	83.51	gold quality
ectocervix	UBERON:0012249	83.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.35	gold quality
left coronary artery	UBERON:0001626	83.30	gold quality
transverse colon	UBERON:0001157	83.26	gold quality
blood	UBERON:0000178	83.17	gold quality
spleen	UBERON:0002106	83.12	gold quality
tibialis anterior	UBERON:0001385	82.85	silver quality
popliteal artery	UBERON:0002250	82.84	gold quality
tibial artery	UBERON:0007610	82.81	gold quality
lymph node	UBERON:0000029	82.77	gold quality
omental fat pad	UBERON:0010414	82.67	gold quality
right coronary artery	UBERON:0001625	82.64	gold quality
peritoneum	UBERON:0002358	82.62	gold quality
lower esophagus	UBERON:0013473	82.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.59	gold quality
left uterine tube	UBERON:0001303	82.43	gold quality
coronary artery	UBERON:0001621	82.37	gold quality
endocervix	UBERON:0000458	82.29	gold quality
telencephalon	UBERON:0001893	82.22	gold quality
aorta	UBERON:0000947	82.19	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.19	gold quality
cerebral cortex	UBERON:0000956	82.16	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.15	gold quality
embryo	UBERON:0000922	82.09	gold quality
biceps brachii	UBERON:0001507	82.04	silver quality
pancreas	UBERON:0001264	82.02	gold quality
deltoid	UBERON:0001476	81.82	silver quality
minor salivary gland	UBERON:0001830	81.72	gold quality
stomach	UBERON:0000945	81.67	gold quality
body of uterus	UBERON:0009853	81.58	gold quality
ascending aorta	UBERON:0001496	81.56	gold quality
thoracic aorta	UBERON:0001515	81.53	gold quality
forebrain	UBERON:0001890	81.49	gold quality
right atrium auricular region	UBERON:0006631	81.47	gold quality
triceps brachii	UBERON:0001509	81.37	silver quality
heart	UBERON:0000948	81.22	gold quality
mouth mucosa	UBERON:0003729	81.09	gold quality
esophagus squamous epithelium	UBERON:0006920	80.90	gold quality
colon	UBERON:0001155	80.88	gold quality
right lobe of thyroid gland	UBERON:0001119	80.82	gold quality
ventricular zone	UBERON:0003053	80.81	gold quality
anatomical system	UBERON:0000467	80.77	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.76	gold quality
large intestine	UBERON:0000059	80.62	gold quality
multicellular organism	UBERON:0000468	80.59	gold quality
material anatomical entity	UBERON:0000465	80.56	gold quality
vermiform appendix	UBERON:0001154	80.56	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.53	gold quality
brain	UBERON:0000955	80.49	gold quality
ovary	UBERON:0000992	80.48	gold quality
descending thoracic aorta	UBERON:0002345	80.41	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	2515.07
E-MTAB-7008	yes	1955.98
E-ANND-3	yes	6.16

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Hippocampal formation	tissue	41.0
Skeletal muscle	tissue	25.2	not detected
Pancreas	tissue	23.8	not detected
Basal ganglia	tissue	21.8	low
Tongue	tissue	21.0
Putamen	tissue	19.8
Lymph node	tissue	19.6	medium
Skin 1	tissue	18.1	not detected
Ventral forebrain	tissue	17.8
Septum	tissue	16.9
Cerebral cortex	tissue	16.3	low
Somatosensory cortex	tissue	16.3
Bone marrow	tissue	16.0	high
Frontal cortex	tissue	15.8
Esophagus	tissue	15.7	not detected
Entorhinal cortex	tissue	15.6
Vagina	tissue	15.2	not detected
Caudate putamen	tissue	15.2
Nucleus accumbens	tissue	15.0
Ovary	tissue	14.9	low
Salivary gland	tissue	14.6	not detected
Motor cortex	tissue	14.6
Retrosplenial and cingulate cortex	tissue	14.6
Spinal cord	tissue	14.4
Superior colliculi	tissue	14.2
Temporal cortex	tissue	14.1
Adrenal gland	tissue	14.0	low
Thalamus	tissue	13.7
Thymus	tissue	13.6
Fallopian tube	tissue	13.6	not detected
Occipital cortex	tissue	13.6
Prefrontal cortex	tissue	13.4
Midbrain	tissue	13.4
Retrosplenial cortex	tissue	13.4
Pons	tissue	13.3
Medulla oblongata	tissue	13.0
Heart muscle	tissue	12.4	high
Amygdala	tissue	12.4
Substantia nigra	tissue	12.3
Appendix	tissue	12.1	medium
Insular cortex	tissue	11.8
Olfactory bulb	tissue	11.7
Postcentral gyrus	tissue	11.6
Spleen	tissue	11.2	high
Breast	tissue	11.1	not detected
Urinary bladder	tissue	11.0	not detected
Colon	tissue	10.9	not detected
Hippocampus	tissue	10.8	low
Locus coeruleus	tissue	10.7
Corpus callosum	tissue	10.4
Stomach 1	tissue	10.2	not detected
Duodenum	tissue	10.2	not detected
Hypothalamus	tissue	10.0
Liver	tissue	10.0	not detected
Thyroid gland	tissue	9.8	not detected
Periaqueductal gray	tissue	9.8
Tonsil	tissue	9.6	high
Small intestine	tissue	9.4	not detected
Adipose tissue	tissue	8.6	not detected
Cerebellum	tissue	8.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Dorsal hippocampus (41.0), Ventral hippocampus (31.4), Dorsal funiculus (white matter) (19.8), Lateral funiculus (white matter) (19.7), Occipital cortex (white matter) (19.4).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting EXOSC5 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

10 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-4443	98.02	66.25	1928

Functional genomics

gnomAD constraint: pLI 0.00184, LOEUF 1.14, missense Z -0.0345 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000221233 — one region, missense o/e 0.96. DepMap (CRISPR cell-line fitness): dependent in 92.3% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): KYO-1 (-1.32), 697 (-1.297), BL-70 (-1.278), KMS-26 (-1.25), MHH-ES-1 (-1.24), NH-6 (-1.22), KP-4 (-1.212), HEL 92.1.7 (-1.202), SF-295 (-1.177), LOU-NH91 (-1.169), NIH:OVCAR-3 (-1.161), NCI-H1975 (-1.153), SNU-1033 (-1.151), D341 Med (-1.142), TEN (-1.14).

Literature-anchored findings (GeneRIF, showing 9)

• association of hCsl4p with the exosome is mediated by protein-protein interactions with hRrp42p and hRrp46p (PMID:11812149)
• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. (PMID:12419256)
• These results in our study indicates gene silencing of SOCS1 remarkably enhanced the cytotoxicity efficiency of CML28 DNA vaccine in DCs. (PMID:16815301)
• rAAV/CML28-transduced DCs vaccine may serve as a feasible approach for the treatment of CML28-associated cancers. (PMID:18157497)
• Results suggest that Rrp46 forms a homodimer separately from exosome complexes and, depending on species, is a structural component of the machinery that cleaves DNA during apoptosis. (PMID:20660080)
• Further, subcellular co-localization assay showed that the two proteins could co-localize in the cytoplasm of K562 cells, but WT1/CML28 complexes were not detected by using immunoprecipitation. (PMID:23392705)
• The roles of Prdx1 and Exosc5 in host defense mechanisms in HBV infection. (PMID:30567989)
• Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness. (PMID:32504085)
• Risk of sudden cardiac death in EXOSC5-related disease. (PMID:34089229)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	exosc5	ENSDARG00000040557
mus_musculus	Exosc5	ENSMUSG00000061286
rattus_norvegicus	Exosc5	ENSRNOG00000020635
drosophila_melanogaster	Rrp46	FBGN0037815
caenorhabditis_elegans		WBGENE00000798

Paralogs (2): EXOSC4 (ENSG00000178896), EXOSC6 (ENSG00000223496)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q7YRA3	97.6%	Diamond
Arabidopsis thaliana	Q9LX74	64.8%	Diamond
Oryza sativa Japonica Group	Q84T68	64.3%	Diamond
Archaeoglobus fulgidus DSM 4304	O29757	64.1%	Diamond
Schizosaccharomyces pombe 972h-	O42894	36.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TMEM91	protein-coding	641649
TGFB1	protein-coding	7040
B9D2	protein-coding	80776
CCDC97	protein-coding	90324
BCKDHA	protein-coding	593
B3GNT8	protein-coding	374907
DMAC2	protein-coding	55101
HNRNPUL1	protein-coding	11100
ERICH4	protein-coding	100170765

Protein

Protein identifiers

Exosome complex component RRP46 — Q9NQT4 (reviewed: Q9NQT4)

Alternative names: Chronic myelogenous leukemia tumor antigen 28, Exosome component 5, Ribosomal RNA-processing protein 46, p12B

All UniProt accessions (4): M0R050, M0R102, M0R289, Q9NQT4

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding ‘pervasive’ transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3’ untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. In vitro, EXOSC5 does not bind or digest single-stranded RNA and binds to double-stranded DNA without detectable DNase activity.

Subunit / interactions. Homodimer. Component of the RNA exosome core complex (Exo-9), composed of EXOSC1, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7, EXOSC8 and EXOSC9; within the complex interacts with EXOSC3, EXOSC8, and EXOSC9. The catalytically inactive RNA exosome core complex (Exo-9) associates with the catalytic subunit EXOSC10/RRP6. Exo-9 may associate with DIS3 to form the nucleolar exosome complex, or DIS3L to form the cytoplasmic exosome complex. Exo-9 is formed by a hexameric base ring consisting of the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and a cap ring consisting of EXOSC1, EXOSC2 and EXOSC3. The RNA exosome complex associates with cofactors C1D/RRP47, MPHOSPH6/MPP6 and MTREX/MTR4. Interacts with GTPBP1. Interacts with ZC3HAV1. Interacts with DDX17 only in the presence of ZC3HAV1 in an RNA-independent manner.

Subcellular location. Nucleus. Nucleolus. Cytoplasm.

Tissue specificity. Highly expressed in a variety of hematopoietic and epithelial tumor cell lines, but not in normal hematopoietic tissues or other normal tissue, with the exception of testis.

Disease relevance. Cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC) [MIM:619576] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development and speech delay that are observed in most patients. Disease manifestations are variable and include infantile-onset hypotonia, poor motor development, poor feeding and overall growth, and ataxic gait due to cerebellar ataxia. Additional variable features are dysarthria, nystagmus, variable ocular anomalies, spasticity, hyperreflexia, and non-specific dysmorphic features. Brain imaging shows cerebellar hypoplasia, often with brainstem hypoplasia, enlarged ventricles, delayed myelination, and thin corpus callosum. A significant number of patients develop cardiac conduction defects in childhood or adolescence. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RNase PH family.

RefSeq proteins (1): NP_064543* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001247	ExoRNase_PH_dom1	Domain
IPR015847	ExoRNase_PH_dom2	Domain
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027408	PNPase/RNase_PH_dom_sf	Homologous_superfamily
IPR036345	ExoRNase_PH_dom2_sf	Homologous_superfamily
IPR050080	RNase_PH	Family

Pfam: PF01138, PF03725

UniProt features (28 total): strand 12, sequence variant 6, helix 5, chain 1, region of interest 1, turn 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDB	Title	Method	Resolution (Å)
9G8M	human 80S ribosome bound by a SKI2-exosome complex	ELECTRON MICROSCOPY	3.3
2NN6	Structure of the human RNA exosome composed of Rrp41, Rrp45, Rrp46, Rrp43, Mtr3, Rrp42 …	X-RAY DIFFRACTION	3.35
9G8O	human 40S ribosome bound by a SKI238-exosome complex	ELECTRON MICROSCOPY	3.4
6D6Q	Human nuclear exosome-MTR4 RNA complex - overall reconstruction	ELECTRON MICROSCOPY	3.45
6D6R	Human nuclear exosome-MTR4 RNA complex - composite map after focused reconstruction	ELECTRON MICROSCOPY	3.45
9G8N	80S-bound human Ski2-exosome complex	ELECTRON MICROSCOPY	3.7
6H25	Human nuclear RNA exosome EXO-10-MPP6 complex	ELECTRON MICROSCOPY	3.8
9G8P	40S-bound human SKI2-exosome complex	ELECTRON MICROSCOPY	7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQT4-F1	84.59	0.63

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Congenital malformations, Other congenital malformations, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoli; nucleoplasm

Antibody reliability (HPA): IH approved · IF enhanced

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)

Type	Positions
Phosphoserine	20

Function

Pathways and Gene Ontology

Reactome pathways

7 curated (TAS) of 17; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

17 pathways:

ID	Pathway	Evidence
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress	curated
R-HSA-450385	Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	curated
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA	curated
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol	curated
R-HSA-9930044	Nuclear RNA decay	curated
R-HSA-450513	Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	curated
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease	curated
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-429914	Deadenylation-dependent mRNA decay	—
R-HSA-8953854	Metabolism of RNA	—
R-HSA-381042	PERK regulates gene expression	—
R-HSA-450531	Regulation of mRNA stability by proteins that bind AU-rich elements	—
R-HSA-9938024	Somatic hypermutation of immunoglobulin genes	electronic
R-HSA-381119	Unfolded Protein Response (UPR)	—
R-HSA-72312	rRNA processing	—
R-HSA-8868773	rRNA processing in the nucleus and cytosol	—

MSigDB gene sets: 294 (showing top): GOBP_RIBOSOME_BIOGENESIS, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_SNO_S_RNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, USF_C, GOBP_DNA_MODIFICATION, GOBP_RNA_SURVEILLANCE, GOBP_DEFENSE_RESPONSE_TO_VIRUS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, FISCHER_DREAM_TARGETS, GOMF_EXONUCLEASE_ACTIVITY

GO Biological Process (10): rRNA processing (GO:0006364), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), mRNA catabolic process (GO:0006402), rRNA catabolic process (GO:0016075), U4 snRNA 3’-end processing (GO:0034475), DNA deamination (GO:0045006), defense response to virus (GO:0051607), nuclear mRNA surveillance (GO:0071028), poly(A)-dependent snoRNA 3’-end processing (GO:0071051)

GO Molecular Function (4): 3’-5’-RNA exonuclease activity (GO:0000175), DNA binding (GO:0003677), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (10): nuclear exosome (RNase complex) (GO:0000176), cytoplasmic exosome (RNase complex) (GO:0000177), exosome (RNase complex) (GO:0000178), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), exoribonuclease complex (GO:1905354)

Reactome top-level categories

10 top-level categories:

Category	Pathways
Metabolism of RNA	4
Regulation of mRNA stability by proteins that bind AU-rich elements	3
PERK regulates gene expression	1
Deadenylation-dependent mRNA decay	1
rRNA processing in the nucleus and cytosol	1
Affinity selection of immunoglobulins	1
Cellular responses to stimuli	1
Unfolded Protein Response (UPR)	1
Cellular responses to stress	1
rRNA processing	1

GO top-level categories

34 GO namespaces:

Category	Terms
nuclear lumen	3
cellular anatomical structure	3
rRNA metabolic process	2
RNA catabolic process	2
nucleic acid binding	2
exosome (RNase complex)	2
cytoplasm	2
intracellular anatomical structure	2
RNA processing	1
ribosome biogenesis	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
negative regulation of gene expression	1
mRNA metabolic process	1
snRNA 3’-end processing	1
DNA modification	1
defense response	1
response to virus	1
nuclear-transcribed mRNA catabolic process	1
nuclear RNA surveillance	1
sno(s)RNA 3’-end processing	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
binding	1
nucleus	1
nuclear protein-containing complex	1
exoribonuclease complex	1
chromatin	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
catalytic complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
DNA deamination	BP	direct assay
RNA catabolic process	BP	direct assay
RNA processing	BP	direct assay
defense response to virus	BP	mutant phenotype
mRNA catabolic process	BP	mutant phenotype
cytosol	CC	direct assay
euchromatin	CC	mutant phenotype
exosome (RNase complex)	CC	direct assay
nucleolus	CC	direct assay
nucleus	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,913 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXOSC5	EXOSC7	Q15024	991
EXOSC5	EXOSC1	Q9Y3B2	989
EXOSC5	EXOSC8	Q96B26	988
EXOSC5	EXOSC3	Q9NQT5	988
EXOSC5	EXOSC9	Q06265	962
EXOSC5	EXOSC2	Q13868	941
EXOSC5	SKIC2	Q15477	857
EXOSC5	EXOSC6	Q5RKV6	854
EXOSC5	EXOSC4	Q9NPD3	845
EXOSC5	EXOSC10	Q01780	836
EXOSC5	DIS3	Q9Y2L1	793
EXOSC5	MPHOSPH6	Q99547	770
EXOSC5	C1D	Q13901	767
EXOSC5	MTREX	P42285	736
EXOSC5	DIS3L	Q8TF46	725

IntAct

Human interaction partners of EXOSC5 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 66 partners by confidence:

Partner	Interaction type	MIscore	Records
EXOSC1	physical association	0.970	29
EXOSC8	physical association	0.950	19
EXOSC3	physical association	0.910	5
EXOSC10	association	0.890	3
IKZF3	physical association	0.780	7
BIRC2	physical association	0.720	6
TNFAIP1	physical association	0.720	6
TRIM54	physical association	0.720	6
FCHO1	physical association	0.670	7
FH	physical association	0.660	3
SNW1	physical association	0.660	3
TFIP11	physical association	0.660	3
ZFC3H1	association	0.640	3
REL	physical association	0.560	6
ZNF655	physical association	0.560	5
ACOT11	physical association	0.560	3
ADAMTSL4	physical association	0.560	3
BORCS6	physical association	0.560	3
CALCOCO2	physical association	0.560	3
CCDC88B	physical association	0.560	3
DDIT4L	physical association	0.560	3
DOCK8	physical association	0.560	3
EFHC2	physical association	0.560	3
GOLGA2	physical association	0.560	3
HOXC4	physical association	0.560	3
KCTD13	physical association	0.560	3
KRT13	physical association	0.560	3
KRT27	physical association	0.560	3
KRT31	physical association	0.560	3
KRT34	physical association	0.560	3

BioGRID (300 interactions; top human partners by supporting records): EXOSC1 (Two-hybrid; 20 records), EXOSC8 (Two-hybrid; 16 records), EXOSC3 (Affinity Capture-MS; 13 records), EXOSC10 (Co-fractionation; 8 records), EXOSC2 (Co-fractionation; 8 records), EXOSC4 (Co-fractionation; 8 records), EXOSC7 (Affinity Capture-MS; 7 records), EXOSC9 (Co-fractionation; 7 records), DIS3L (Affinity Capture-MS; 6 records), MPHOSPH6 (Co-fractionation; 6 records), C1D (Affinity Capture-MS; 5 records), EXOSC6 (Co-fractionation; 4 records), RBM7 (Affinity Capture-MS; 4 records), SKIV2L2 (Affinity Capture-MS; 4 records), HBS1L (Reconstituted Complex; 3 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
EXOSC5	“form complex”	Exosome_Complex	binding

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
Exosome	12	EXOSC3, EXOSC6, EXOSC7, EXOSC8, EXOSC1, EXOSC10, EXOSC4, EXOSC5, EXOSC9, MPHOSPH6, DIS3L, EXOSC2
Exosome	11	EXOSC1, EXOSC2, EXOSC6, EXOSC7, EXOSC9, DIS3, EXOSC10, EXOSC3, EXOSC4, EXOSC5, EXOSC8
Exosome	10	EXOSC9, DIS3, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7, EXOSC8, EXOSC1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nuclear RNA decay	5	32.8×	9e-05
Formation of the cornified envelope	5	9.3×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	5	26.9×	1e-04
RNA processing	7	23.9×	6e-06
intermediate filament organization	5	18.8×	4e-04
epithelial cell differentiation	5	13.7×	1e-03
rRNA processing	6	13.3×	4e-04

Disease & clinical

Genetic variants

Variant evidence for EXOSC5: 76 ClinVar records (4 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	54
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3359747	NM_020158.4(EXOSC5):c.525+1G>A	Likely pathogenic	criteria provided, single submitter	1
1300245	NM_020158.4(EXOSC5):c.526-72_689del	Pathogenic	no assertion criteria provided	1
1300246	NM_020158.4(EXOSC5):c.617T>A (p.Leu206His)	Pathogenic	no assertion criteria provided	1
1300247	NM_020158.4(EXOSC5):c.87del (p.His30fs)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore EXOSC5’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 552):

Position(s)	Effect	Δscore	Sites
19:41387512–41387513	donor_loss	1.0000	4
19:41391963–41391964	acceptor_loss	1.0000	5
19:41397179–41397180	donor_loss	1.0000	5
19:41386726–41386727	acceptor_loss	0.9900	4
19:41387512–41387513	donor_loss	0.9900	2
19:41387604–41387605	acceptor_loss	0.9900	5
19:41389763–41389764	donor_loss	0.9900	5
19:41391810	donor_gain	0.9900
19:41391963	acceptor_loss	0.9900
19:41391972	acceptor_gain	0.9900

AlphaMissense

642 missense substitutions predicted likely pathogenic (of 1,501 scored), across 178 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D42	8	0.939	0.966
D168	8	0.926	0.957
D143	8	0.911	0.951
F221	8	0.880	0.962
F183	8	0.846	0.981
F152	8	0.809	0.973
F223	7	0.952	0.993
N135	7	0.930	0.996
E69	7	0.920	0.974
E95	7	0.883	0.969
F47	7	0.870	0.987
Q121	7	0.863	0.965
C102	7	0.831	0.994
D125	7	0.727	0.845
G60	6	0.988	0.998
P61	6	0.971	0.991
G43	6	0.970	0.997
G199	6	0.970	0.991
G85	6	0.946	0.988
G127	6	0.927	0.984

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	3.06e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	4.63e-05
Rectum Adenocarcinoma (TCGA)	favorable	0.000682

Disease associations

OMIM: gene MIM:606492 | disease phenotypes: MIM:619576

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
cerebellar ataxia, brain abnormalities, and cardiac conduction defects	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (3 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

3 panels:

Panel	Rating
Ataxia and cerebellar anomalies - childhood onset	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Fetal anomalies	amber

Mondo (1): cerebellar ataxia, brain abnormalities, and cardiac conduction defects (MONDO:0859200)

Orphanet (1): Neurodevelopmental delay-hypotonia-cerebellar ataxia-cardiac conduction defects syndrome (Orphanet:641361)

HPO phenotypes

49 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000340	Sloping forehead
HP:0000426	Prominent nasal bridge
HP:0000448	Prominent nose
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0000692	Tooth malposition
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001302	Pachygyria
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0001653	Mitral regurgitation
HP:0002015	Dysphagia
HP:0002120	Cerebral cortical atrophy
HP:0002187	Profound intellectual disability
HP:0002310	Orofacial dyskinesia
HP:0002415	Leukodystrophy
HP:0002540	Inability to walk
HP:0002650	Scoliosis
HP:0003429	CNS hypomyelination
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0004411	Deviated nasal septum
HP:0005180	Tricuspid regurgitation
HP:0011712	Complete right bundle branch block
HP:0011968	Feeding difficulties
HP:0012385	Camptodactyly
HP:0012471	Thick vermilion border
HP:0030084	Clinodactyly
HP:0032794	Myoclonic seizure

GWAS associations

1 associations:

Study	Trait	p-value
GCST90000025_106	Appendicular lean mass	4e-15

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066390 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression, affects binding (+1 more)	3
perfluorooctane sulfonic acid	increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Plant Extracts	affects cotreatment, decreases expression, increases expression	2
Rotenone	decreases expression	2
Cyclosporine	increases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression, increases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases oxidation, affects cotreatment, increases abundance	1
Cisplatin	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases 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
CHEMBL5651395	Binding	Binding affinity to human EXOSC5 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for EXOSC5 across ~30M SureChEMBL compounds — explore on Sugi Predict.