EXOSC6

Summary

EXOSC6 (exosome component 6, HGNC:19055) is a protein-coding gene on chromosome 16q22.1, encoding Exosome complex component MTR3 (Q5RKV6). 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 99.1% of cancer cell lines).

This gene product constitutes one of the subunits of the multisubunit particle called exosome, which mediates mRNA degradation. The composition of human exosome is similar to its yeast counterpart. This protein is homologous to the yeast Mtr3 protein. Its exact function is not known, however, it has been shown using a cell-free RNA decay system that the exosome is required for rapid degradation of unstable mRNAs containing AU-rich elements (AREs), but not for poly(A) shortening. The exosome does not recognize ARE-containing mRNAs on its own, but requires ARE-binding proteins that could interact with the exosome and recruit it to unstable mRNAs, thereby promoting their rapid degradation.

Source: NCBI Gene 118460 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 73 total
• GTEx eGene: eQTL in 50 tissues, sQTL in 0 (q < 0.05)
• Cancer dependency (DepMap): dependent in 99.1% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.04 (LoF-tolerant), LOEUF 1.95 (unconstrained)
• MANE Select transcript: NM_058219
• Notable: 73 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19055
Approved symbol	EXOSC6
Name	exosome component 6
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MTR3, hMtr3p, Mtr3p, EAP4, p11
Ensembl gene	ENSG00000223496
Ensembl biotype	protein_coding
OMIM	606490
Entrez	118460

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

MANE Select: ENST00000435634

ENST00000435634

RefSeq mRNA: 1 — MANE Select: NM_058219 NM_058219

CCDS: CCDS10887

Canonical transcript exons

ENST00000435634 — 1 exons

Exon	Start	End
ENSE00001653290	70246778	70251940

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.8753 / max 100.1468, expressed in 1763 samples.

Highest expression (Bgee): buccal mucosa cell, endothelial cell, Brodmann (1909) area 23, postcentral gyrus, Brodmann (1909) area 46.

Genetic regulation across tissues (GTEx eQTL / sQTL)

EXOSC6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 50 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 50 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.4e-236	-1.00	16:70251998:A:G
Artery Tibial	eqtl	3.7e-184	-0.93	16:70251998:A:G
Adipose Subcutaneous	eqtl	3.1e-178	-0.89	16:70251998:A:G
Skin Sun Exposed Lower leg	eqtl	7.5e-178	-0.77	16:70251998:A:G
Muscle Skeletal	eqtl	1.4e-175	-0.95	16:70251998:A:G
Lung	eqtl	1.3e-153	-0.76	16:70251998:A:G
Esophagus Muscularis	eqtl	1.9e-149	-0.90	16:70251998:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.8e-142	-0.66	16:70251998:A:G
Adipose Visceral Omentum	eqtl	1.9e-138	-0.78	16:70251998:A:G
Artery Aorta	eqtl	7.8e-133	-0.91	16:70251998:A:G
Heart Atrial Appendage	eqtl	2.4e-128	-1.02	16:70251998:A:G
Thyroid	eqtl	1.0e-123	-0.71	16:70251998:A:G
Esophagus Mucosa	eqtl	3.2e-119	-0.70	16:70251998:A:G
Colon Transverse	eqtl	7.3e-115	-0.91	16:70251998:A:G
Heart Left Ventricle	eqtl	1.4e-114	-1.02	16:70251998:A:G
Breast Mammary Tissue	eqtl	1.4e-112	-0.81	16:70251998:A:G
Esophagus Gastroesophageal Junction	eqtl	2.1e-107	-0.91	16:70251998:A:G
Colon Sigmoid	eqtl	1.1e-101	-0.84	16:70251998:A:G
Whole Blood	eqtl	5.0e-89	-0.44	16:70251998:A:G
Stomach	eqtl	9.4e-80	-0.91	16:70251998:A:G

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
157925	16.8753	1763

Top tissues by expression

showing 100 of 242 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.23	gold quality
endothelial cell	CL:0000115	93.90	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.17	gold quality
postcentral gyrus	UBERON:0002581	90.04	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.77	gold quality
primary visual cortex	UBERON:0002436	89.54	gold quality
superior frontal gyrus	UBERON:0002661	89.27	gold quality
middle temporal gyrus	UBERON:0002771	89.07	gold quality
parietal lobe	UBERON:0001872	88.70	gold quality
occipital lobe	UBERON:0002021	87.47	gold quality
calcaneal tendon	UBERON:0003701	87.22	gold quality
entorhinal cortex	UBERON:0002728	86.84	gold quality
pons	UBERON:0000988	86.82	gold quality
cortical plate	UBERON:0005343	86.81	gold quality
lateral globus pallidus	UBERON:0002476	86.79	gold quality
oviduct epithelium	UBERON:0004804	86.16	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.72	gold quality
nucleus accumbens	UBERON:0001882	84.53	gold quality
cerebral cortex	UBERON:0000956	84.51	gold quality
cerebellum	UBERON:0002037	84.45	gold quality
caudate nucleus	UBERON:0001873	84.15	gold quality
cerebellar cortex	UBERON:0002129	84.08	gold quality
cerebellar hemisphere	UBERON:0002245	84.06	gold quality
putamen	UBERON:0001874	83.99	gold quality
neocortex	UBERON:0001950	83.95	gold quality
frontal cortex	UBERON:0001870	83.89	gold quality
brain	UBERON:0000955	83.69	gold quality
forebrain	UBERON:0001890	83.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.31	gold quality
Ammon’s horn	UBERON:0001954	83.17	gold quality
temporal lobe	UBERON:0001871	83.11	gold quality
anterior cingulate cortex	UBERON:0009835	82.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	82.80	gold quality
adrenal tissue	UBERON:0018303	82.71	gold quality
right frontal lobe	UBERON:0002810	82.69	gold quality
prefrontal cortex	UBERON:0000451	82.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.58	gold quality
bone marrow cell	CL:0002092	82.22	gold quality
colonic epithelium	UBERON:0000397	82.18	gold quality
hypothalamus	UBERON:0001898	81.98	gold quality
right adrenal gland cortex	UBERON:0035827	81.77	gold quality
ganglionic eminence	UBERON:0004023	81.72	gold quality
gastrocnemius	UBERON:0001388	81.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.52	gold quality
muscle of leg	UBERON:0001383	81.43	gold quality
left adrenal gland	UBERON:0001234	81.29	gold quality
substantia nigra pars compacta	UBERON:0001965	81.12	gold quality
ventricular zone	UBERON:0003053	81.08	gold quality
leukocyte	CL:0000738	81.00	gold quality
right adrenal gland	UBERON:0001233	80.98	gold quality
lateral nuclear group of thalamus	UBERON:0002736	80.93	gold quality
adrenal gland	UBERON:0002369	80.87	gold quality
granulocyte	CL:0000094	80.77	gold quality
monocyte	CL:0000576	80.76	gold quality
amygdala	UBERON:0001876	80.74	gold quality
substantia nigra	UBERON:0002038	80.71	gold quality
cauda epididymis	UBERON:0004360	80.70	gold quality
midbrain	UBERON:0001891	80.60	gold quality
islet of Langerhans	UBERON:0000006	80.53	gold quality
left adrenal gland cortex	UBERON:0035825	80.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.41	gold quality
adenohypophysis	UBERON:0002196	80.41	gold quality
secondary oocyte	CL:0000655	80.27	gold quality
upper leg skin	UBERON:0004262	80.27	gold quality
corpus epididymis	UBERON:0004359	80.26	gold quality
oocyte	CL:0000023	80.21	gold quality
adrenal cortex	UBERON:0001235	80.18	gold quality
globus pallidus	UBERON:0001875	80.03	gold quality
caput epididymis	UBERON:0004358	80.02	gold quality
pancreas	UBERON:0001264	79.91	gold quality
fallopian tube	UBERON:0003889	79.90	gold quality
ventral tegmental area	UBERON:0002691	79.77	silver quality
body of pancreas	UBERON:0001150	79.64	gold quality
pituitary gland	UBERON:0000007	79.62	gold quality
skin of abdomen	UBERON:0001416	79.52	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	79.46	gold quality
tendon	UBERON:0000043	79.26	gold quality
spinal cord	UBERON:0002240	79.22	gold quality
adult organism	UBERON:0007023	79.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	79.20	gold quality
skin of leg	UBERON:0001511	79.17	gold quality
medial globus pallidus	UBERON:0002477	78.96	gold quality
dorsal plus ventral thalamus	UBERON:0001897	78.85	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	78.84	gold quality
descending thoracic aorta	UBERON:0002345	78.79	gold quality
zone of skin	UBERON:0000014	78.76	gold quality
right lobe of liver	UBERON:0001114	78.74	gold quality
spleen	UBERON:0002106	78.69	gold quality
superior vestibular nucleus	UBERON:0007227	78.56	gold quality
lower esophagus muscularis layer	UBERON:0035833	78.53	gold quality
lower esophagus	UBERON:0013473	78.51	gold quality
lymph node	UBERON:0000029	78.48	gold quality
popliteal artery	UBERON:0002250	78.45	gold quality
tibial artery	UBERON:0007610	78.45	gold quality
ovary	UBERON:0000992	78.44	gold quality
subthalamic nucleus	UBERON:0001906	78.42	gold quality
mucosa of transverse colon	UBERON:0004991	78.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.33	gold quality
anatomical system	UBERON:0000467	78.21	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.70
E-MTAB-6678	yes	4.76
E-GEOD-98556	no	587.49
E-GEOD-70580	no	183.85

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 74 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Postcentral gyrus	tissue	59.8
Nucleus accumbens	tissue	58.1
Locus coeruleus	tissue	57.5
Hippocampus	tissue	52.0
Choroid plexus	tissue	35.3
Bone marrow	tissue	11.1
Thyroid gland	tissue	10.3
Pituitary gland	tissue	9.8
Skin 1	tissue	9.8
Retina	tissue	8.4
Lymph node	tissue	8.1
Skeletal muscle	tissue	8.0
Spleen	tissue	8.0
Adrenal gland	tissue	7.6
Parathyroid gland	tissue	7.3
Tonsil	tissue	7.2
Vagina	tissue	6.8
Liver	tissue	6.7
Ovary	tissue	6.4
Adipose tissue	tissue	6.3
Pancreas	tissue	6.3
Thymus	tissue	6.3
Urinary bladder	tissue	6.0
Prostate	tissue	6.0
Breast	tissue	5.9
Stomach 1	tissue	5.8
Kidney	tissue	5.7
Fallopian tube	tissue	5.6
Appendix	tissue	5.6
Esophagus	tissue	5.5
Epididymis	tissue	5.5
Heart muscle	tissue	5.4
Smooth muscle	tissue	5.3
Colon	tissue	5.1
Rectum	tissue	4.9
Endometrium 1	tissue	4.9
Tongue	tissue	4.8
Duodenum	tissue	4.8
Placenta	tissue	4.7
Cervix	tissue	4.6
Seminal vesicle	tissue	4.6
Small intestine	tissue	4.6
Lung	tissue	4.5
Salivary gland	tissue	4.4
Cerebellum	tissue	4.0
Gallbladder	tissue	3.8
Testis	tissue	3.7
Thalamus	tissue	3.1
Hypothalamus	tissue	3.1
Olfactory bulb	tissue	3.1
Basal ganglia	tissue	3.0
Midbrain	tissue	3.0
Hippocampal formation	tissue	3.0
Septum	tissue	3.0
Cerebral cortex	tissue	2.9
Ventral forebrain	tissue	2.9
Somatosensory cortex	tissue	2.9
Entorhinal cortex	tissue	2.8
Occipital cortex	tissue	2.8
Pons	tissue	2.7

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Flocculonodular lobe (64.3), Pontine nuclei (64.3), Ventral posteromedial thalamic nucleus (64.2), Lateral amygdala (64.0), Nucleus raphe magnus (64.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

Targeting EXOSC6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 50 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-6868-5P	99.06	65.69	1284

Functional genomics

gnomAD constraint: pLI 0.0391, LOEUF 1.95, missense Z -1.3 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000435634 — one region, missense o/e 1.29. DepMap (CRISPR cell-line fitness): dependent in 99.1% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): ONCO-DG-1 (-2.773), SNU-1033 (-2.566), LOU-NH91 (-2.439), NCI-H226 (-2.402), MJ (-2.366), SNU-840 (-2.363), NIH:OVCAR-3 (-2.361), OCUM-1 (-2.355), OPM-2 (-2.332), IST-MES2 (-2.255), SNU-1079 (-2.248), NCI-H2887 (-2.213), UOK101 (-2.187), HCC2429 (-2.171), OCI-AML3 (-2.168).

Literature-anchored findings (GeneRIF, showing 2)

• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. (PMID:12419256)
• We have recently identified increased expression of p11 genes that implicate fibrinolysis in ALD progression. (PMID:18289715)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	exosc6	ENSDARG00000036060
mus_musculus	Exosc6	ENSMUSG00000109941
rattus_norvegicus	Exosc6	ENSRNOG00000018582
drosophila_melanogaster	Mtr3	FBGN0036916
caenorhabditis_elegans		WBGENE00000202

Paralogs (2): EXOSC5 (ENSG00000077348), EXOSC4 (ENSG00000178896)

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
Pyrococcus horikoshii OT3	O59223	97.2%	Diamond
Pyrococcus abyssi GE5	Q9V119	97.2%	Diamond
Pyrococcus furiosus DSM 3638	Q8U0L9	96.8%	Diamond
Thermococcus onnurineus NA1	B6YSI2	94.4%	Diamond
Thermococcus kodakarensis KOD1	Q5JIR6	94.0%	Diamond
Caenorhabditis briggsae	A8WQQ5	93.8%	Diamond
Pyrobaculum arsenaticum DSM 13514	A4WM67	93.5%	Diamond
Pyrobaculum aerophilum str. IM2	Q8ZVM9	93.5%	Diamond
Pyrobaculum calidifontis JCM 11548	A3MUP1	92.7%	Diamond
Pyrobaculum neutrophilum V24Sta	B1Y978	92.7%	Diamond
Thermococcus gammatolerans EJ3	C5A2B9	92.0%	Diamond
Pyrobaculum islandicum DSM 4184	A1RST0	91.9%	Diamond
Thermoplasma acidophilum DSM 1728	Q9HIP2	89.9%	Diamond
Sulfurisphaera tokodaii str. 7	Q975G8	86.8%	Diamond
Saccharolobus solfataricus P2	Q9UXC2	84.0%	Diamond
Cenarchaeum symbiosum A	A0RXU1	77.9%	Diamond
Nitrosopumilus maritimus SCM1	A9A5C9	77.9%	Diamond
Methanopyrus kandleri AV19	Q8TYC1	70.6%	Diamond
Hyperthermus butylicus DSM 5456	A2BKC0	67.1%	Diamond
Methanothermobacter thermautotrophicus str. Delta H	O26779	65.8%	Diamond
Xenopus tropicalis	Q28F19	58.3%	Diamond
Arabidopsis thaliana	Q9SP08	50.7%	Diamond
Schizosaccharomyces pombe 972h-	Q9P7R3	36.3%	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
AARS1	protein-coding	16
CLEC18C	protein-coding	283971
DDX19B	protein-coding	11269
DDX19A	protein-coding	55308
ST3GAL2	protein-coding	6483
PDPR	protein-coding	55066
DDX19A-DT	ncRNA	100506083

Protein

Protein identifiers

Exosome complex component MTR3 — Q5RKV6 (reviewed: Q5RKV6)

Alternative names: Exosome component 6, mRNA transport regulator 3 homolog, p11

All UniProt accessions (1): Q5RKV6

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.

Subunit / interactions. 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 EXOSC1, EXOSC7 and EXOSC8. The catalytically inactive Exo-9 may associate 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 EXOSC10/RRP6, C1D/RRP47, MPHOSPH6/MPP6 and MTREX/MTR4.

Subcellular location. Cytoplasm. Nucleus. Nucleolus.

Similarity. Belongs to the RNase PH family.

RefSeq proteins (1): NP_478126* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001247	ExoRNase_PH_dom1	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

UniProt features (27 total): strand 14, helix 7, turn 4, chain 1, region of interest 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-Q5RKV6-F1	80.97	0.42

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

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: 169 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_REGULATION_OF_DNA_RECOMBINATION, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, chr16q22, GOBP_B_CELL_ACTIVATION, GOMF_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_SNO_S_RNA_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_B_CELL_MEDIATED_IMMUNITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY

GO Biological Process (10): rRNA processing (GO:0006364), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), rRNA catabolic process (GO:0016075), U4 snRNA 3’-end processing (GO:0034475), DNA deamination (GO:0045006), isotype switching (GO:0045190), nuclear mRNA surveillance (GO:0071028), poly(A)-dependent snoRNA 3’-end processing (GO:0071051), DNA metabolic process (GO:0006259)

GO Molecular Function (1): RNA binding (GO:0003723)

GO Cellular Component (8): nuclear exosome (RNase complex) (GO:0000176), cytoplasmic exosome (RNase complex) (GO:0000177), exosome (RNase complex) (GO:0000178), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), cytoplasm (GO:0005737)

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

28 GO namespaces:

Category	Terms
nuclear lumen	3
cellular anatomical structure	3
rRNA metabolic process	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
RNA catabolic process	1
snRNA 3’-end processing	1
DNA modification	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
nuclear-transcribed mRNA catabolic process	1
nuclear RNA surveillance	1
sno(s)RNA 3’-end processing	1
nucleic acid metabolic process	1
nucleic acid binding	1
nucleus	1
nuclear protein-containing complex	1
exoribonuclease complex	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
DNA deamination	BP	direct assay
RNA catabolic process	BP	direct assay
RNA processing	BP	direct assay
cytosol	CC	direct assay
exosome (RNase complex)	CC	direct assay
nucleolus	CC	direct assay
nucleus	CC	direct assay
RNA binding	MF	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 1,583 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXOSC6	EXOSC7	Q15024	991
EXOSC6	EXOSC1	Q9Y3B2	989
EXOSC6	EXOSC8	Q96B26	989
EXOSC6	EXOSC3	Q9NQT5	988
EXOSC6	EXOSC9	Q06265	963
EXOSC6	EXOSC2	Q13868	939
EXOSC6	EXOSC5	Q9NQT4	854
EXOSC6	SKIC2	Q15477	827
EXOSC6	EXOSC4	Q9NPD3	823
EXOSC6	EXOSC10	Q01780	822
EXOSC6	DIS3	Q9Y2L1	796
EXOSC6	MPHOSPH6	Q99547	762
EXOSC6	DIS3L	Q8TF46	750
EXOSC6	MTREX	P42285	747
EXOSC6	C1D	Q13901	706

IntAct

Human interaction partners of EXOSC6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
AICDA	association	0.350	1
EXOSC10	association	0.350	1

BioGRID (196 interactions; top human partners by supporting records): EXOSC7 (Affinity Capture-MS; 9 records), EXOSC1 (Affinity Capture-MS; 7 records), EXOSC3 (Affinity Capture-MS; 6 records), EXOSC8 (Affinity Capture-MS; 6 records), EXOSC4 (Co-fractionation; 5 records), EXOSC10 (Proximity Label-MS; 4 records), EXOSC2 (Co-fractionation; 4 records), EXOSC5 (Co-fractionation; 4 records), MPHOSPH6 (Co-fractionation; 4 records), AICDA (Affinity Capture-MS; 3 records), DIS3L (Affinity Capture-MS; 3 records), EXOSC9 (Co-fractionation; 3 records), IFI16 (Affinity Capture-MS; 3 records), ANLN (Affinity Capture-MS; 2 records), C1D (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
EXOSC6	“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

Disease & clinical

Genetic variants

Variant evidence for EXOSC6: 73 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	1
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 10 predictions of 89):

Position(s)	Effect	Δscore	Sites
16:70250889	donor_gain	0.9500
16:70250978	donor_gain	0.9500
16:70250979	donor_gain	0.9100
16:70250910	donor_gain	0.8700
16:70248054	acceptor_gain	0.8500
16:70247233	acceptor_gain	0.8400
16:70250968	donor_gain	0.8400
16:70248055	acceptor_gain	0.8100
16:70250955	donor_gain	0.7900
16:70250896	donor_gain	0.7600

AlphaMissense

520 missense substitutions predicted likely pathogenic (of 1,671 scored), across 156 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
D178	8	0.957	0.992
F105	8	0.936	0.993
D198	8	0.863	0.953
D4	8	0.819	0.901
D171	8	0.763	0.928
E56	7	0.897	0.975
M216	7	0.891	0.952
C64	7	0.868	0.989
G51	6	0.968	0.992
K61	6	0.946	0.996
P217	6	0.903	0.984
C98	6	0.899	0.970
M176	6	0.890	0.961
F100	6	0.880	0.981
G155	6	0.877	0.965
C248	6	0.870	0.991
R7	6	0.836	0.973
W237	6	0.830	0.931
P11	6	0.812	0.924
G68	6	0.802	0.955

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Squamous Cell Carcinoma (validation)	favorable	0.000292
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000442

Disease associations

OMIM: gene MIM:606490 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST010703_143	Brain morphology (MOSTest)	2e-40
GCST010725_22	Malaria	6e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects cotreatment, increases abundance, increases expression	5
Cyclosporine	decreases expression, increases expression	4
Cadmium Chloride	increases expression	2
methylmercuric chloride	decreases expression	1
sodium arsenate	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
hydroquinone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
2-palmitoylglycerol	increases expression	1
entinostat	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
nutlin 3	increases secretion, affects cotreatment	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Naphthoquinones	increases expression	1
Ribonucleotides	affects binding	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1WQ	HAP1 EXOSC6 (-) 1	Cancer cell line	Male
CVCL_E1WR	HAP1 EXOSC6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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