EXOSC4

Summary

EXOSC4 (exosome component 4, HGNC:18189) is a protein-coding gene on chromosome 8q24.3, encoding Exosome complex component RRP41 (Q9NPD3). 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 99.4% of cancer cell lines).

Enables mRNA 3’-UTR AU-rich region binding activity. Involved in several processes, including DNA deamination; maturation of 5.8S rRNA; and nuclear-transcribed mRNA catabolic process. Acts upstream of or within defense response to virus. Located in cytosol; euchromatin; and nuclear lumen. Part of exosome (RNase complex).

Source: NCBI Gene 54512 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 35 total
• GTEx eGene: eQTL in 5 tissues, sQTL in 4 (q < 0.05)
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.36 (unconstrained)
• MANE Select transcript: NM_019037
• Interaction hub: 2,212 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18189
Approved symbol	EXOSC4
Name	exosome component 4
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	hRrp41p, FLJ20591, Rrp41p, RRP41, RRP41A, Ski6p, SKI6, p12A
Ensembl gene	ENSG00000178896
Ensembl biotype	protein_coding
OMIM	606491
Entrez	54512

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

MANE Select: ENST00000316052

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

ENST00000316052, ENST00000525936, ENST00000527954, ENST00000905027, ENST00000917254, ENST00000917255, ENST00000917256, ENST00001120921, ENST00001139128

RefSeq mRNA: 1 — MANE Select: NM_019037 NM_019037

CCDS: CCDS6414

Canonical transcript exons

ENST00000316052 — 3 exons

Exon	Start	End
ENSE00001254956	144079943	144080149
ENSE00001292034	144078672	144078899
ENSE00001300596	144080242	144080648

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 96.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.4050 / max 216.1845, expressed in 1813 samples.

Highest expression (Bgee): testis, mucosa of transverse colon, apex of heart, adrenal gland, adrenal gland cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

EXOSC4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 5 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	4.8e-29	-0.43	8:144073555:A:C
Minor Salivary Gland	eqtl	1.2e-06	+0.46	8:144127038:A:G
Small Intestine Terminal Ileum	eqtl	1.6e-02	-1.09	8:144301703:G:A
Brain Cerebellum	eqtl	2.0e-02	+0.47	8:143706374:C:G
Breast Mammary Tissue	sqtl	2.0e-02	-1.07	8:144950153:C:T
Brain Nucleus accumbens basal ganglia	eqtl	2.0e-02	-0.17	8:143696661:G:A
Testis	sqtl	3.0e-02	-1.09	8:144083655:C:G
Brain Anterior cingulate cortex BA24	sqtl	3.4e-02	-1.97	8:143505620:C:T
Nerve Tibial	sqtl	4.6e-02	+0.44	8:144069890:T:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
91467	17.6132	1807
91466	4.2481	1539
91468	0.5054	287
91465	0.0383	12

Top tissues by expression

showing 100 of 282 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	96.62	gold quality
right testis	UBERON:0004534	96.54	gold quality
testis	UBERON:0000473	93.65	gold quality
mucosa of transverse colon	UBERON:0004991	91.76	gold quality
apex of heart	UBERON:0002098	91.18	gold quality
right adrenal gland	UBERON:0001233	90.21	gold quality
left adrenal gland	UBERON:0001234	89.81	gold quality
right adrenal gland cortex	UBERON:0035827	89.75	gold quality
left adrenal gland cortex	UBERON:0035825	89.63	gold quality
right lobe of liver	UBERON:0001114	88.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.34	gold quality
adrenal cortex	UBERON:0001235	88.24	gold quality
body of stomach	UBERON:0001161	88.17	gold quality
anterior cingulate cortex	UBERON:0009835	87.60	gold quality
prefrontal cortex	UBERON:0000451	87.47	gold quality
cingulate cortex	UBERON:0003027	87.45	gold quality
esophagus mucosa	UBERON:0002469	87.23	gold quality
stromal cell of endometrium	CL:0002255	87.01	gold quality
nucleus accumbens	UBERON:0001882	86.97	gold quality
adrenal gland	UBERON:0002369	86.97	gold quality
right atrium auricular region	UBERON:0006631	86.88	gold quality
lower esophagus mucosa	UBERON:0035834	86.83	gold quality
left coronary artery	UBERON:0001626	86.44	gold quality
adenohypophysis	UBERON:0002196	86.38	gold quality
right frontal lobe	UBERON:0002810	86.31	gold quality
esophagus	UBERON:0001043	86.24	gold quality
caudate nucleus	UBERON:0001873	86.17	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.95	gold quality
lower esophagus	UBERON:0013473	85.94	gold quality
left uterine tube	UBERON:0001303	85.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.85	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.78	gold quality
skin of leg	UBERON:0001511	85.70	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.70	gold quality
gastrocnemius	UBERON:0001388	85.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.68	gold quality
transverse colon	UBERON:0001157	85.65	gold quality
skin of abdomen	UBERON:0001416	85.47	gold quality
amygdala	UBERON:0001876	85.40	gold quality
putamen	UBERON:0001874	85.37	gold quality
coronary artery	UBERON:0001621	85.34	gold quality
granulocyte	CL:0000094	85.27	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.27	gold quality
heart left ventricle	UBERON:0002084	85.23	gold quality
metanephros cortex	UBERON:0010533	85.23	gold quality
minor salivary gland	UBERON:0001830	85.15	gold quality
monocyte	CL:0000576	84.99	gold quality
thoracic aorta	UBERON:0001515	84.95	gold quality
ascending aorta	UBERON:0001496	84.90	gold quality
descending thoracic aorta	UBERON:0002345	84.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.85	gold quality
mononuclear cell	CL:0000842	84.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.73	gold quality
spleen	UBERON:0002106	84.73	gold quality
leukocyte	CL:0000738	84.70	gold quality
cardiac ventricle	UBERON:0002082	84.68	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.63	gold quality
right coronary artery	UBERON:0001625	84.60	gold quality
aorta	UBERON:0000947	84.59	gold quality
muscle of leg	UBERON:0001383	84.47	gold quality
popliteal artery	UBERON:0002250	84.47	gold quality
tibial artery	UBERON:0007610	84.47	gold quality
stomach	UBERON:0000945	84.46	gold quality
cardiac atrium	UBERON:0002081	84.36	gold quality
omental fat pad	UBERON:0010414	84.25	gold quality
cortical plate	UBERON:0005343	84.22	gold quality
peritoneum	UBERON:0002358	84.21	gold quality
pituitary gland	UBERON:0000007	83.81	gold quality
spinal cord	UBERON:0002240	83.80	gold quality
blood	UBERON:0000178	83.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.64	gold quality
heart	UBERON:0000948	83.62	gold quality
upper lobe of left lung	UBERON:0008952	83.60	gold quality
right lobe of thyroid gland	UBERON:0001119	83.49	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.47	gold quality
ectocervix	UBERON:0012249	83.46	gold quality
mouth mucosa	UBERON:0003729	83.43	gold quality
neocortex	UBERON:0001950	83.12	gold quality
cerebellar hemisphere	UBERON:0002245	83.10	gold quality
cerebellar cortex	UBERON:0002129	83.05	gold quality
body of pancreas	UBERON:0001150	83.00	gold quality
saliva-secreting gland	UBERON:0001044	82.85	gold quality
mucosa of stomach	UBERON:0001199	82.84	gold quality
zone of skin	UBERON:0000014	82.80	gold quality
tibial nerve	UBERON:0001323	82.73	gold quality
left lobe of thyroid gland	UBERON:0001120	82.67	gold quality
colon	UBERON:0001155	82.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.57	gold quality
frontal cortex	UBERON:0001870	82.56	gold quality
body of uterus	UBERON:0009853	82.51	gold quality
fundus of stomach	UBERON:0001160	82.42	gold quality
right ovary	UBERON:0002118	82.11	gold quality
large intestine	UBERON:0000059	82.06	gold quality
cerebellum	UBERON:0002037	81.96	gold quality
ganglionic eminence	UBERON:0004023	81.85	gold quality
forebrain	UBERON:0001890	81.81	gold quality
telencephalon	UBERON:0001893	81.81	gold quality
endocervix	UBERON:0000458	81.79	gold quality
adult mammalian kidney	UBERON:0000082	81.51	gold quality
hypothalamus	UBERON:0001898	81.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Putamen	tissue	39.9
Basal ganglia	tissue	33.8	low
Cerebral cortex	tissue	31.4	medium
Motor cortex	tissue	31.4
Pons	tissue	28.7
Hippocampal formation	tissue	28.3
Entorhinal cortex	tissue	28.3
Ventral forebrain	tissue	27.4
Somatosensory cortex	tissue	27.4
Prefrontal cortex	tissue	27.2
Retrosplenial and cingulate cortex	tissue	26.9
Thalamus	tissue	26.4
Temporal cortex	tissue	26.1
Retrosplenial cortex	tissue	25.6
Insular cortex	tissue	25.6
Midbrain	tissue	25.5
Occipital cortex	tissue	25.4
Hypothalamus	tissue	24.8
Substantia nigra	tissue	24.6
Septum	tissue	24.2
Nucleus accumbens	tissue	23.9
Testis	tissue	23.3	medium
Salivary gland	tissue	23.2	low
Superior colliculi	tissue	23.2
Choroid plexus	tissue	22.9
Periaqueductal gray	tissue	22.0
Medulla oblongata	tissue	21.8
Hippocampus	tissue	21.5	medium
Corpus callosum	tissue	21.4
Locus coeruleus	tissue	21.1
Amygdala	tissue	20.6
Cerebellum	tissue	20.0	medium
Postcentral gyrus	tissue	19.4
Pituitary gland	tissue	17.9
Spinal cord	tissue	17.8
Frontal cortex	tissue	15.6
Olfactory bulb	tissue	15.5
Vagina	tissue	15.0	medium
Liver	tissue	14.4	not detected
Caudate putamen	tissue	14.0
Bone marrow	tissue	12.9	medium
Pancreas	tissue	12.3	medium
Duodenum	tissue	11.9	medium
Skeletal muscle	tissue	11.4	medium
Stomach 1	tissue	11.3	medium
Seminal vesicle	tissue	11.1	medium
Adrenal gland	tissue	11.1	medium
Skin 1	tissue	10.9	medium
Adipose tissue	tissue	10.6	not detected
Urinary bladder	tissue	10.6	medium
Lymph node	tissue	10.4	low
Colon	tissue	10.1	medium
Heart muscle	tissue	9.9	low
Prostate	tissue	9.6	medium
Esophagus	tissue	9.4	medium
Spleen	tissue	9.3	not detected
Appendix	tissue	9.2	medium
Parathyroid gland	tissue	9.1	medium
Kidney	tissue	9.0	low
Thymus	tissue	9.0

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Area parastriata, superior (34.9), Dorsal hippocampus (25.7), Caudate nucleus (23.8), Cerebellar cortex (23.8), Nucleus ambiguus (23.8).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 3.64e-06, LOEUF 1.36, missense Z -0.518 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000316052 — one region, missense o/e 1.01. DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SNU-245 (-2.486), EFM-19 (-2.418), 253J (-2.364), OPM-2 (-2.317), MHH-NB-11 (-2.172), L-363 (-2.124), KP-4 (-2.109), SK-N-DZ (-2.071), OCI-LY-19 (-2.054), SNU-478 (-2.052), SNU-1077 (-2.041), D283 Med (-2.028), SW579 (-2.016), KP-N-YN (-2.014), COV318 (-2.01).

Literature-anchored findings (GeneRIF, showing 5)

• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. (PMID:12419256)
• Knock-down of hRrp41p or hRrp4p but not PM/Scl-100 or PM/Scl-75 leads to codepletion of other subunits. (PMID:17545563)
• Findings show that EXOSC4 is highly expressed in colorectal cancer (CRC) tumors and cell lines and demonstrate its oncogenic role in development and progression of CRC. (PMID:30155936)
• RNA Exosome Component EXOSC4 Amplified in Multiple Cancer Types Is Required for the Cancer Cell Survival. (PMID:35008922)
• RUNX3 exerts tumor-suppressive role through inhibiting EXOSC4 expression. (PMID:38913281)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	exosc4	ENSDARG00000103432
mus_musculus	Exosc4	ENSMUSG00000034259
rattus_norvegicus	Exosc4	ENSRNOG00000012348
drosophila_melanogaster	Ski6	FBGN0032487
caenorhabditis_elegans		WBGENE00007201

Paralogs (2): EXOSC5 (ENSG00000077348), 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
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 volcanium GSS1	Q97BZ5	89.9%	Diamond
Thermoplasma acidophilum DSM 1728	Q9HIP2	89.9%	Diamond
Sulfolobus acidocaldarius DSM 639	Q4JB27	86.8%	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
Aeropyrum pernix K1	Q9YC03	67.1%	Diamond
Methanothermobacter thermautotrophicus str. Delta H	O26779	65.8%	Diamond
Archaeoglobus fulgidus DSM 4304	O29757	64.1%	Diamond
Methanosarcina mazei Go1	Q8PTT8	62.5%	Diamond
Xenopus tropicalis	Q28F19	58.3%	Diamond
Arabidopsis thaliana	Q9SP08	50.7%	Diamond
Schizosaccharomyces pombe 972h-	O42872	43.4%	Diamond
Saccharomyces cerevisiae S288C	P46948	39.3%	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
MIR6847	ncRNA	102465510
OPLAH	protein-coding	26873
GPAA1	protein-coding	8733
MIR6846	ncRNA	102465509
CYC1	protein-coding	1537
SHARPIN	protein-coding	81858
SPATC1	protein-coding	375686
PARP10	protein-coding	84875
MAF1	protein-coding	84232

Protein

Protein identifiers

Exosome complex component RRP41 — Q9NPD3 (reviewed: Q9NPD3)

Alternative names: Exosome component 4, Ribosomal RNA-processing protein 41, p12A

All UniProt accessions (3): E9PI41, E9PPI9, Q9NPD3

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. EXOSC4 binds to ARE-containing RNAs.

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 EXOSC2, EXOSC7 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 DDX60. Interacts with DIS3; the interaction is direct.

Subcellular location. Cytoplasm. Nucleus. Nucleolus. Nucleoplasm.

Similarity. Belongs to the RNase PH family.

RefSeq proteins (1): NP_061910* (*=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 (27 total): strand 14, helix 7, turn 3, initiator methionine 1, chain 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-Q9NPD3-F1	90.34	0.71

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm; vesicles

Antibody reliability (HPA): IH approved · IF supported

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
N-acetylalanine	2

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: 185 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, ELVIDGE_HYPOXIA_DN, GOBP_RIBOSOME_BIOGENESIS, MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOMF_NUCLEASE_ACTIVITY, MODULE_151, GOBP_SNO_S_RNA_METABOLIC_PROCESS, MATTIOLI_MGUS_VS_PCL, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_503, GOBP_DNA_MODIFICATION

GO Biological Process (13): maturation of 5.8S rRNA (GO:0000460), nuclear-transcribed mRNA catabolic process (GO:0000956), rRNA processing (GO:0006364), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), rRNA catabolic process (GO:0016075), positive regulation of cell growth (GO:0030307), U4 snRNA 3’-end processing (GO:0034475), DNA deamination (GO:0045006), defense response to virus (GO:0051607), nuclear mRNA surveillance (GO:0071028), histone mRNA catabolic process (GO:0071044), poly(A)-dependent snoRNA 3’-end processing (GO:0071051)

GO Molecular Function (4): 3’-5’-RNA exonuclease activity (GO:0000175), RNA binding (GO:0003723), mRNA 3’-UTR AU-rich region binding (GO:0035925), 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

40 GO namespaces:

Category	Terms
nuclear lumen	3
cellular anatomical structure	3
rRNA metabolic process	2
nuclear-transcribed mRNA catabolic process	2
exosome (RNase complex)	2
cytoplasm	2
intracellular anatomical structure	2
rRNA processing	1
mRNA catabolic process	1
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
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
snRNA 3’-end processing	1
DNA modification	1
defense response	1
response to virus	1
nuclear RNA surveillance	1
histone mRNA metabolic process	1
sno(s)RNA 3’-end processing	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
nucleic acid binding	1
mRNA 3’-UTR binding	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) — 17 of 27 annotations. The rest are phylogenetic / computational / electronic (IEA).

17 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
histone mRNA catabolic process	BP	mutant phenotype
maturation of 5.8S rRNA	BP	mutant phenotype
nuclear mRNA surveillance	BP	mutant phenotype
nuclear-transcribed mRNA catabolic process	BP	mutant phenotype
positive regulation of cell growth	BP	mutant phenotype
cytoplasm	CC	direct assay
cytosol	CC	direct assay
euchromatin	CC	mutant phenotype
exosome (RNase complex)	CC	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
mRNA 3’-UTR AU-rich region binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,212 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXOSC4	EXOSC7	Q15024	987
EXOSC4	EXOSC1	Q9Y3B2	985
EXOSC4	EXOSC3	Q9NQT5	977
EXOSC4	EXOSC8	Q96B26	976
EXOSC4	EXOSC9	Q06265	938
EXOSC4	EXOSC2	Q13868	929
EXOSC4	SKIC2	Q15477	849
EXOSC4	EXOSC5	Q9NQT4	845
EXOSC4	EXOSC10	Q01780	839
EXOSC4	EXOSC6	Q5RKV6	823
EXOSC4	DIS3	Q9Y2L1	809
EXOSC4	DIS3L	Q8TF46	735
EXOSC4	MTREX	P42285	720
EXOSC4	C1D	Q13901	712
EXOSC4	XRN1	Q8IZH2	665

IntAct

Human interaction partners of EXOSC4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 32 partners by confidence:

Partner	Interaction type	MIscore	Records
EXOSC2	physical association	0.910	3
EXOSC9	physical association	0.900	4
EXOSC7	physical association	0.900	3
EXOSC10	association	0.840	3
POLE2	physical association	0.560	5
LNX1	physical association	0.560	3
SDCBP	physical association	0.560	3
ZFC3H1	association	0.530	3
MTREX	association	0.530	1
TET3	physical association	0.400	1
RPS3	association	0.350	1
EXOSC1	physical association	0.000	2
AKR1A1	physical association	0.000	1
DHPS	physical association	0.000	1
DXO	physical association	0.000	1
EEF1A1	physical association	0.000	1
EXOSC3	physical association	0.000	1
FAHD1	physical association	0.000	1
GADD45GIP1	physical association	0.000	1
GTF2IRD1	physical association	0.000	1
HLA-B	physical association	0.000	1
HNRNPD	physical association	0.000	1
LRRC47	physical association	0.000	1
LRRC8D	physical association	0.000	1
LUM	physical association	0.000	1
MPZL1	physical association	0.000	1
NEK1	physical association	0.000	1
RSRC1	physical association	0.000	1
SKIC2	physical association	0.000	1
SLIT2	physical association	0.000	1

BioGRID (346 interactions; top human partners by supporting records): EXOSC2 (Co-fractionation; 15 records), EXOSC9 (Co-fractionation; 15 records), EXOSC7 (Affinity Capture-MS; 13 records), EXOSC3 (Affinity Capture-MS; 12 records), EXOSC10 (Co-fractionation; 11 records), EXOSC1 (Co-fractionation; 10 records), EXOSC5 (Co-fractionation; 8 records), EXOSC8 (Affinity Capture-MS; 8 records), DIS3L (Affinity Capture-MS; 7 records), MPHOSPH6 (Co-fractionation; 7 records), EXOSC6 (Co-fractionation; 5 records), SKIV2L2 (Affinity Capture-MS; 4 records), HBS1L (Reconstituted Complex; 3 records), RBM7 (Affinity Capture-MS; 3 records), AICDA (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
EXOSC4	“form complex”	Exosome_Complex	binding

Protein complexes (CORUM) (4)

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

4 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
mRNA decay complex (UPF1, UPF2, UPF3B, DCP2, XRN1, XRN2, EXOSC2, EXOSC4, EXOSC10, PARN)	10	XRN1, XRN2, DCP2, EXOSC2, EXOSC4, PARN, UPF1, UPF3B, EXOSC10, UPF2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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
mRNA decay by 3’ to 5’ exoribonuclease	6	152.9×	7e-11
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	5	113.3×	2e-08
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	5	113.3×	2e-08
KSRP (KHSRP) binds and destabilizes mRNA	5	113.3×	2e-08
Nuclear RNA decay	9	99.2×	1e-14
ATF4 activates genes in response to endoplasmic reticulum stress	5	72.8×	1e-07
Major pathway of rRNA processing in the nucleolus and cytosol	8	17.6×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA catabolic process	5	119.7×	2e-08
RNA catabolic process	8	113.9×	5e-13
RNA processing	8	54.7×	5e-11
rRNA processing	7	31.0×	5e-08

Disease & clinical

Genetic variants

Variant evidence for EXOSC4: 35 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	2
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 24 predictions of 221):

Position(s)	Effect	Δscore	Sites
8:144079941–144079942	acceptor_loss	1.0000	6
8:144080150	donor_loss	1.0000	3
8:144080240–144080241	acceptor_loss	1.0000	4
8:144078871	donor_gain	0.9900
8:144080151	donor_loss	0.9900	2
8:144078900	donor_loss	0.9800	3
8:144080240	acceptor_loss	0.9800
8:144078901	donor_loss	0.9700	2
8:144080237	acceptor_gain	0.9700
8:144078904	donor_loss	0.9600

AlphaMissense

645 missense substitutions predicted likely pathogenic (of 1,548 scored), across 192 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
F81	8	0.973	0.999
D172	8	0.970	0.988
D15	8	0.968	0.987
D122	8	0.948	0.981
D131	8	0.938	0.984
D93	8	0.877	0.954
F107	8	0.859	0.990
F32	8	0.850	0.962
D36	8	0.843	0.943
D148	8	0.791	0.941
E177	7	0.961	0.983
C74	7	0.912	0.996
N140	7	0.886	0.993
D155	7	0.785	0.956
G44	6	0.983	0.995
G54	6	0.983	0.997
G37	6	0.979	0.997
R23	6	0.970	0.997
P55	6	0.970	0.989
G16	6	0.969	0.991

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
Glioblastoma Multiforme (validation)	favorable	0.000122
Ovary Serous Cystadenocarcinoma (TCGA)	favorable	0.000893

Disease associations

OMIM: gene MIM:606491 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (1): complex neurodevelopmental disorder (MONDO:0100038)

GWAS associations

4 associations:

Study	Trait	p-value
GCST012353_30	Serum metabolite concentrations in chronic kidney disease	2e-22
GCST009798_78	Asthma	1e-8
GCST008115_38	Bipolar I disorder	2e-8
GCST008103_69	Bipolar disorder	1e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0009963	bipolar I disorder

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725126 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.90	Kd	1268	nM	CHEMBL5653589
5.90	ED50	1268	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148352: Binding affinity to human EXOSC4 incubated for 45 mins by Kinobead based pull down assay	kd	1.2684	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
Hydrogen Peroxide	decreases expression, affects expression, affects cotreatment	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
deguelin	decreases expression	1
K 7174	decreases expression	1
fenpyroximate	decreases expression	1
thifluzamide	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases expression	1
Cannabidiol	increases expression	1
Clozapine	increases expression	1
Diazinon	increases methylation	1
Ethyl Methanesulfonate	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651394	Binding	Binding affinity to human EXOSC4 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.

2 trials:

NCT	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for EXOSC4 across ~30M SureChEMBL compounds — explore on Sugi Predict.