USP19

Summary

USP19 (ubiquitin specific peptidase 19, HGNC:12617) is a protein-coding gene on chromosome 3p21.31, encoding Ubiquitin carboxyl-terminal hydrolase 19 (O94966). Deubiquitinating enzyme that regulates the degradation of various proteins by removing ubiquitin moieties, thereby preventing their proteasomal degradation.

Protein ubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. This dynamic process, involving ubiquitin conjugating enzymes and deubiquitinating enzymes, adds and removes ubiquitin. Deubiquitinating enzymes are cysteine proteases that specifically cleave ubiquitin from ubiquitin-conjugated protein substrates. This protein is a ubiquitin protein ligase and plays a role in muscle wasting. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10869 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 238 total — 2 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001199161

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12617
Approved symbol	USP19
Name	ubiquitin specific peptidase 19
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0891, ZMYND9
Ensembl gene	ENSG00000172046
Ensembl biotype	protein_coding
OMIM	614471
Entrez	10869

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000306026, ENST00000398888, ENST00000398896, ENST00000417901, ENST00000434032, ENST00000453664, ENST00000464931, ENST00000465902, ENST00000483667, ENST00000689715, ENST00000691288, ENST00000692912, ENST00000693111, ENST00000698200

RefSeq mRNA: 40 — MANE Select: NM_001199161 NM_001199160, NM_001199161, NM_001199162, NM_001351098, NM_001351099, NM_001351100, NM_001351101, NM_001351102, NM_001351103, NM_001351104, NM_001351105, NM_001351106, NM_001351107, NM_001351108, NM_001389594, NM_001389595, NM_001389596, NM_001389597, NM_001389598, NM_001389599, NM_001389600, NM_001389601, NM_001389602, NM_001389603, NM_001389604, NM_001389605, NM_001389606, NM_001389607, NM_001389608, NM_001400288, NM_001400290, NM_001400292, NM_001400293, NM_001400294, NM_001400295, NM_001400296, NM_001400297, NM_001400298, NM_001400299, NM_006677

CCDS: CCDS43090, CCDS56254, CCDS56255, CCDS56256, CCDS93270, CCDS93271, CCDS93272, CCDS93273, CCDS93274

Canonical transcript exons

ENST00000417901 — 27 exons

Exon	Start	End
ENSE00001332009	49116047	49116162
ENSE00001332015	49117059	49117361
ENSE00001606143	49112489	49112629
ENSE00001609810	49112284	49112402
ENSE00001614451	49113992	49114093
ENSE00001616912	49114763	49114873
ENSE00001632289	49115724	49115944
ENSE00001660429	49110711	49110863
ENSE00001669321	49111500	49111813
ENSE00001671927	49114959	49115117
ENSE00001721670	49108050	49108528
ENSE00001726624	49115228	49115361
ENSE00001729929	49114174	49114284
ENSE00001751597	49111911	49112048
ENSE00001764245	49110184	49110362
ENSE00001765596	49115444	49115639
ENSE00001781832	49110950	49111166
ENSE00001802617	49111255	49111365
ENSE00003508264	49116727	49116943
ENSE00003521834	49110444	49110604
ENSE00003582612	49117437	49117570
ENSE00003585455	49117657	49117830
ENSE00003598428	49116451	49116607
ENSE00003611080	49116280	49116351
ENSE00003619586	49117947	49118120
ENSE00003876020	49119022	49119281
ENSE00003923501	49120756	49120823

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 94.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.2096 / max 178.6412, expressed in 1810 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42217	10.5934	1791
42218	5.9958	1703
42216	0.6204	337

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	94.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.60	gold quality
muscle of leg	UBERON:0001383	94.27	gold quality
right uterine tube	UBERON:0001302	94.05	gold quality
right lobe of thyroid gland	UBERON:0001119	93.84	gold quality
right adrenal gland cortex	UBERON:0035827	93.75	gold quality
granulocyte	CL:0000094	93.68	gold quality
apex of heart	UBERON:0002098	93.51	gold quality
right adrenal gland	UBERON:0001233	93.49	gold quality
metanephros cortex	UBERON:0010533	93.23	gold quality
body of tongue	UBERON:0011876	93.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.11	gold quality
left adrenal gland	UBERON:0001234	92.88	gold quality
left lobe of thyroid gland	UBERON:0001120	92.83	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.80	gold quality
adrenal cortex	UBERON:0001235	92.79	gold quality
left adrenal gland cortex	UBERON:0035825	92.70	gold quality
body of uterus	UBERON:0009853	92.66	gold quality
transverse colon	UBERON:0001157	92.60	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.52	gold quality
cerebellar hemisphere	UBERON:0002245	92.47	gold quality
mucosa of transverse colon	UBERON:0004991	92.44	gold quality
cerebellar cortex	UBERON:0002129	92.33	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.32	gold quality
lower esophagus	UBERON:0013473	92.30	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.26	gold quality
body of stomach	UBERON:0001161	92.25	gold quality
thyroid gland	UBERON:0002046	92.24	gold quality
fundus of stomach	UBERON:0001160	92.19	gold quality
skin of leg	UBERON:0001511	92.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting USP19, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-2861	95.24	65.47	1056

Literature-anchored findings (GeneRIF, showing 26)

• USP19 is the first example of a membrane-anchored deubiquitinating enzymes involved in the turnover of endoplasmic-reticulum-associated degradation substrates. (PMID:19465887)
• ability of USP19 to regulate cell proliferation and p27(Kip1) levels; complete loss of USP19 function on cell growth may arise as a result of oncogenic transformation of cells. (PMID:21264218)
• The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2. (PMID:21849505)
• ubiquitin-specific protease-19 (USP19) interacts with components of the hypoxia pathway including HIF-1alpha and rescues it from degradation independent of its catalytic activity (PMID:22128162)
• experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system against viruses (PMID:22810585)
• USP19 interacts with the ubiquitin ligases SIAH1 and SIAH2, which promote USP19 ubiquitylation and degradation by the proteasome. (PMID:23500468)
• These results clarify the role of USP19 in ERAD and suggest a novel DUB regulation that involves chaperone association and membrane integration (PMID:24356957)
• Expression of USP19 correlates with that of MuRF1 and MAFbx/atrogin-1 in skeletal muscles (PMID:26048142)
• In conjunction with HSP90, the cytoplasmic USP19 may play a key role in triage decision for the disease-related polyQ-expanded substrates, suggesting a function of USP19 in quality control of misfolded proteins by regulating their protein levels (PMID:26808260)
• USP19 positively regulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. (PMID:26988033)
• The regulation of CORO2A through the deubiquitinating activity of USP19 affected the transcriptional repression activity of the retinoic acid receptor (RAR), suggesting that USP19 may be involved in the regulation of RAR-mediated adipogenesis. (PMID:27129179)
• USP19 is a key factor in modulating DNA damage repair by targeting HDAC1/2 K63-linked ubiquitination, cells with deletion or decreased expression of USP19 might cause genome instability and even contribute to tumorigenesis. (PMID:27517492)
• HRD1 is a novel substrate for USP19. USP19 negatively regulates the ubiquitination of HRD1 and prevents it from undergoing proteasomal degradation. (PMID:27827840)
• findings establish USP19 is a negative regulator of the cellular type I IFN antiviral response to enterovirus 71 (EV71) infection; through the decrease of K63-linked polyubiquitination of TRAF3, USP19 suppresses cellular type I IFN signaling, supporting EV71 propagation in host cells (PMID:28391724)
• HSP90 interacts with Htt-N90 on the N-terminal amphipathic alpha-helix, and then recruits USP19 to modulate the protein level and aggregation of Htt-N90. (PMID:29093475)
• USP19 modulates GR levels and in so doing may modulate both insulin and glucocorticoid signaling, two critical pathways that control protein turnover in muscle and overall glucose homeostasis. (PMID:29901692)
• USP19 mRNA expression in human adipose tissue was positively correlated with the expression of important adipocyte genes in abdominal fat depots, but not subcutaneous fat depots. (PMID:30386869)
• USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth. (PMID:30700749)
• BAP1 is highly positively correlated with RBM15B and USP19 expression in invasive breast carcinoma, UM, and colon adenocarcinoma (PMID:30716094)
• Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma. (PMID:32236633)
• USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites. (PMID:33978709)
• Dual role of deubiquitinating enzyme USP19 regulates mitotic progression and tumorigenesis by stabilizing survivin. (PMID:35918893)
• Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants. (PMID:35987969)
• Opposing USP19 splice variants in TGF-beta signaling and TGF-beta-induced epithelial-mesenchymal transition of breast cancer cells. (PMID:36646950)
• The deubiquitinating enzyme USP19 facilitates hepatocellular carcinoma progression through stabilizing YAP. (PMID:37832781)
• Deubiquitinating Enzyme USP19 Regulates Ferroptosis and Mitochondrial Damage in SH-SY5Y Cells by Targeting the NOX4 Protein. (PMID:38943386)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp19	ENSDARG00000004132
mus_musculus	Usp19	ENSMUSG00000006676
rattus_norvegicus	Usp19	ENSRNOG00000049531

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 19 — O94966 (reviewed: O94966)

Alternative names: Deubiquitinating enzyme 19, Ubiquitin thioesterase 19, Ubiquitin-specific-processing protease 19, Zinc finger MYND domain-containing protein 9

All UniProt accessions (9): O94966, A0A0A0MR08, A0A590UK03, A0A8I5KRW4, A0A8I5KT08, A0A8I5KV50, A0A8I5KXK1, A0A8V8TN96, E7ESU0

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme that regulates the degradation of various proteins by removing ubiquitin moieties, thereby preventing their proteasomal degradation. Stabilizes RNF123, which promotes CDKN1B degradation and contributes to cell proliferation. Decreases the levels of ubiquitinated proteins during skeletal muscle formation and acts to repress myogenesis. Modulates transcription of major myofibrillar proteins. Also involved in turnover of endoplasmic-reticulum-associated degradation (ERAD) substrates. Mechanistically, deubiquitinates and thereby stabilizes several E3 ligases involved in the ERAD pathway including SYVN1 or MARCHF6. Regulates the stability of other E3 ligases including BIRC2/c-IAP1 and BIRC3/c-IAP2 by preventing their ubiquitination. Required for cells to mount an appropriate response to hypoxia by rescuing HIF1A from degradation in a non-catalytic manner and by mediating the deubiquitination of FUNDC1. Attenuates mitochondrial damage and ferroptosis by targeting and stabilizing NADPH oxidase 4/NOX4. Negatively regulates TNF- and IL-1beta-triggered NF-kappa-B activation by hydrolyzing ‘Lys-27’- and ‘Lys-63’-linked polyubiquitin chains from MAP3K7. Modulates also the protein level and aggregation of polyQ-expanded huntingtin/HTT through HSP90AA1.

Subunit / interactions. Interacts with RNF123. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with HIF1A (via N-terminus). Interacts (via N-terminus) with HSP90AA1; this interaction activates the deubiquitinase activity of USP19.

Subcellular location. Endoplasmic reticulum membrane.

Domain organisation. Contains two CS (CHORD and Sgt1) domains, namely CS1 and CS2, in its N-terminus and a catalytic USP domain (USPD).

Similarity. Belongs to the peptidase C19 family.

Isoforms (7)

UniProt ID	Names	Canonical?
O94966-1	1	yes
O94966-2	2
O94966-3	3
O94966-4	4
O94966-5	5
O94966-6	6
O94966-7	7

RefSeq proteins (40): NP_001186089, NP_001186090, NP_001186091, NP_001338027, NP_001338028, NP_001338029, NP_001338030, NP_001338031, NP_001338032, NP_001338033, NP_001338034, NP_001338035, NP_001338036, NP_001338037, NP_001376523, NP_001376524, NP_001376525, NP_001376526, NP_001376527, NP_001376528, NP_001376529, NP_001376530, NP_001376531, NP_001376532, NP_001376533, NP_001376534, NP_001376535, NP_001376536, NP_001376537, NP_001387217, NP_001387219, NP_001387221, NP_001387222, NP_001387223, NP_001387224, NP_001387225, NP_001387226, NP_001387227, NP_001387228, NP_006668 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR002893	Znf_MYND	Domain
IPR007052	CS_dom	Domain
IPR008978	HSP20-like_chaperone	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF01753, PF04969, PF16602

UniProt features (76 total): strand 26, binding site 8, splice variant 8, compositionally biased region 6, helix 5, region of interest 4, turn 4, sequence conflict 3, domain 3, topological domain 2, active site 2, chain 1, transmembrane region 1, modified residue 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4X3G	X-RAY DIFFRACTION	2.34
1WH0	SOLUTION NMR
6K7W	SOLUTION NMR
6KHV	SOLUTION NMR
6KQV	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94966-F1	69.32	0.34

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 506 (nucleophile); 1165 (proton acceptor)

Ligand- & substrate-binding residues (8): 791; 794; 808; 811; 817; 821; 829; 833

Post-translational modifications (1): 244

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 164 (showing top): MORF_RAGE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_SKELETAL_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GCM_ZNF198, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, MARTINEZ_RB1_TARGETS_DN, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (10): protein deubiquitination (GO:0016579), regulation of protein stability (GO:0031647), response to endoplasmic reticulum stress (GO:0034976), ERAD pathway (GO:0036503), negative regulation of skeletal muscle tissue development (GO:0048642), protein stabilization (GO:0050821), positive regulation of cell cycle process (GO:0090068), regulation of cellular response to hypoxia (GO:1900037), regulation of ERAD pathway (GO:1904292), proteolysis (GO:0006508)

GO Molecular Function (8): cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), Hsp90 protein binding (GO:0051879), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
regulation of biological quality	1
cellular response to stress	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
skeletal muscle tissue development	1
negative regulation of striated muscle tissue development	1
regulation of skeletal muscle tissue development	1
regulation of protein stability	1
regulation of cell cycle process	1
cell cycle process	1
positive regulation of cell cycle	1
cellular response to hypoxia	1
regulation of cellular response to stress	1
ERAD pathway	1
regulation of proteasomal protein catabolic process	1
regulation of response to endoplasmic reticulum stress	1
protein metabolic process	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
heat shock protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP19	RNF123	Q5XPI4	894
USP19	USP13	Q92995	723
USP19	BIRC3	Q13489	705
USP19	ZUP1	Q96AP4	671
USP19	USP14	P54578	637
USP19	USP7	Q93009	582
USP19	HSP90AB1	P08238	573
USP19	HSP90AA1	P07900	572
USP19	MYSM1	Q5VVJ2	565
USP19	USP28	Q96RU2	558
USP19	USP25	Q9UHP3	558
USP19	HSPA4	P34932	554
USP19	ATXN3	P54252	528
USP19	YOD1	Q5VVQ6	524
USP19	USP15	Q9Y4E8	517

IntAct

86 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSP90AA1	CHUK	psi-mi:“MI:0914”(association)	0.670
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
	USP19	psi-mi:“MI:0915”(physical association)	0.550
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
HSP90AA1	USP19	psi-mi:“MI:0914”(association)	0.530
HSP90AB1	USP19	psi-mi:“MI:0914”(association)	0.530
FKBP6	EEF2K	psi-mi:“MI:0914”(association)	0.530
USP19	CFTR	psi-mi:“MI:0914”(association)	0.480
	BIN1	psi-mi:“MI:0914”(association)	0.460
HOOK2	USP19	psi-mi:“MI:0407”(direct interaction)	0.440
WWC1	USP19	psi-mi:“MI:0407”(direct interaction)	0.440
USP19	H3-4	psi-mi:“MI:0915”(physical association)	0.400
APBA2	USP19	psi-mi:“MI:0915”(physical association)	0.400
		psi-mi:“MI:0914”(association)	0.350
NEURL4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
USP19		psi-mi:“MI:0914”(association)	0.350
USP7		psi-mi:“MI:0914”(association)	0.350

BioGRID (241): USP19 (Affinity Capture-MS), USP19 (Affinity Capture-MS), USP19 (Affinity Capture-MS), USP19 (Affinity Capture-MS), USP19 (Co-fractionation), HSP90AA1 (Affinity Capture-Western), STUB1 (Affinity Capture-Western), HSP90AA1 (Reconstituted Complex), USP19 (Affinity Capture-Western), USP19 (Affinity Capture-Western), USP19 (Affinity Capture-Western), HDAC1 (Affinity Capture-Western), HDAC2 (Affinity Capture-Western), SYVN1 (Affinity Capture-Western), USP19 (Co-crystal Structure)

ESM2 similar proteins: A2A5N8, A7MBB4, B1B1A0, B2KF05, D3ZWK4, E1C2V1, E9Q3T6, O15060, O43283, O70445, O94966, P0C6P5, P97433, Q0P4M4, Q1HKZ5, Q1LVK9, Q2PFD7, Q3UPF5, Q5DW34, Q5FVG2, Q5R8X7, Q5SW75, Q5TKR9, Q60592, Q63553, Q6P0Q8, Q6ZPI0, Q76I76, Q76I79, Q7TNN8, Q7Z2W4, Q80TF6, Q811L6, Q811P8, Q8BLB7, Q8BRB7, Q8BZ21, Q8CHB8, Q8K3Y6, Q8NA19

Diamond homologs: A0A0R4IB93, A0JM59, A1CIL1, A1CW53, A2XDG4, A3AF13, A5PN09, A6QNM7, A7Z056, B1WBD7, B2GUZ1, B8NSV5, D3ZJ96, F6Z5C0, O22207, O60079, O94966, Q0CT11, Q0E2F9, Q0VA64, Q13107, Q2HJE4, Q2UUG8, Q3UJD6, Q3V0C5, Q4VSI4, Q5I043, Q5R5Z6, Q5RCD3, Q5ZM45, Q60MK8, Q6A4J8, Q6J1Y9, Q6PAW2, Q6U7I1, Q6ZQ93, Q70CQ2, Q76LT8, Q7JKC3, Q84WU2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 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
SARS-CoV-2 activates/modulates innate and adaptive immune responses	6	8.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	8	10.3×	5e-04
protein stabilization	8	6.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	194
Likely benign	18
Benign	3

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
375397	NM_001199161.2(USP19):c.1660G>T (p.Val554Leu)	Pathogenic
375398	NM_001199161.2(USP19):c.1572G>T (p.Glu524Asp)	Pathogenic

SpliceAI

4517 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49110359:CAGC:C	acceptor_gain	1.0000
3:49110363:C:CC	acceptor_gain	1.0000
3:49110442:AC:A	donor_gain	1.0000
3:49110443:CC:C	donor_gain	1.0000
3:49110443:CCCA:C	donor_gain	1.0000
3:49110446:A:AC	donor_gain	1.0000
3:49110447:C:CC	donor_gain	1.0000
3:49110447:CGTCA:C	donor_gain	1.0000
3:49110451:A:AC	donor_gain	1.0000
3:49110452:C:CC	donor_gain	1.0000
3:49110460:A:AC	donor_gain	1.0000
3:49110461:C:CC	donor_gain	1.0000
3:49110462:TGC:T	donor_gain	1.0000
3:49110517:T:TA	donor_gain	1.0000
3:49110603:TCCT:T	acceptor_loss	1.0000
3:49110605:CT:C	acceptor_loss	1.0000
3:49110620:A:T	acceptor_gain	1.0000
3:49110623:C:CT	acceptor_gain	1.0000
3:49110624:A:T	acceptor_gain	1.0000
3:49110706:CTTA:C	donor_loss	1.0000
3:49110708:TA:T	donor_loss	1.0000
3:49110709:A:AC	donor_gain	1.0000
3:49110709:ACC:A	donor_loss	1.0000
3:49110710:C:CA	donor_gain	1.0000
3:49110710:CCTA:C	donor_gain	1.0000
3:49110710:CCTAA:C	donor_gain	1.0000
3:49110859:AGTAC:A	acceptor_gain	1.0000
3:49110860:GTAC:G	acceptor_gain	1.0000
3:49110861:TAC:T	acceptor_gain	1.0000
3:49110862:AC:A	acceptor_gain	1.0000

AlphaMissense

8988 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:49110282:A:C	Y1211D	1.000
3:49110287:A:G	L1209P	1.000
3:49110287:A:T	L1209H	1.000
3:49110344:T:A	D1190V	1.000
3:49110344:T:C	D1190G	1.000
3:49110344:T:G	D1190A	1.000
3:49110345:C:G	D1190H	1.000
3:49110356:C:G	R1186P	1.000
3:49110358:C:A	W1185C	1.000
3:49110358:C:G	W1185C	1.000
3:49110360:A:G	W1185R	1.000
3:49110360:A:T	W1185R	1.000
3:49110491:G:T	A1168D	1.000
3:49110492:C:G	A1168P	1.000
3:49110498:A:G	Y1166H	1.000
3:49110499:G:C	H1165Q	1.000
3:49110499:G:T	H1165Q	1.000
3:49110501:G:C	H1165D	1.000
3:49110518:C:T	G1159E	1.000
3:49110523:G:C	H1157Q	1.000
3:49110523:G:T	H1157Q	1.000
3:49110525:G:C	H1157D	1.000
3:49110533:A:T	V1154D	1.000
3:49110536:G:T	A1153D	1.000
3:49110537:C:G	A1153P	1.000
3:49110542:A:G	L1151P	1.000
3:49110740:C:A	K1120N	1.000
3:49110740:C:G	K1120N	1.000
3:49110742:T:C	K1120E	1.000
3:49110764:A:C	F1112L	1.000

dbSNP variants (sampled 300 via entrez): RS1000394127 (3:49109339 C>G), RS1000439231 (3:49119069 T>C), RS1000541682 (3:49121030 G>A,C), RS1002044524 (3:49111890 G>C,T), RS1002257073 (3:49118216 G>A,T), RS1002330949 (3:49110996 G>C), RS1002394317 (3:49117980 C>A,T), RS1002501947 (3:49112192 C>G,T), RS1002612067 (3:49117128 C>T), RS1002644071 (3:49107905 G>A,C,T), RS1002780523 (3:49107665 C>G), RS1003011704 (3:49120622 C>G), RS1003044277 (3:49120782 C>T), RS1003104519 (3:49110434 G>A,C), RS1003260415 (3:49119812 C>T)

Disease associations

OMIM: gene MIM:614471 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): long QT syndrome (MONDO:0002442)

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST011702_5	Smoking cessation	1.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004319	smoking cessation

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523156 (SINGLE PROTEIN)

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

ChEMBL bioactivities

412 potent at pChembl≥5 of 593 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	EC50	9.9	nM	CHEMBL5087368
7.48	EC50	32.8	nM	CHEMBL5087368
7.31	IC50	49	nM	CHEMBL5428753
7.24	IC50	58	nM	CHEMBL5429248
7.13	IC50	74	nM	CHEMBL5396358
6.96	IC50	110	nM	CHEMBL5433263
6.96	IC50	110	nM	CHEMBL5396766
6.92	IC50	120	nM	CHEMBL5417864
6.85	IC50	140	nM	CHEMBL5432985
6.82	IC50	150	nM	CHEMBL5439024
6.82	IC50	150	nM	CHEMBL5428250
6.72	IC50	190	nM	CHEMBL5439171
6.68	IC50	210	nM	CHEMBL5431080
6.66	IC50	220	nM	CHEMBL5403806
6.55	IC50	280	nM	CHEMBL5429133
6.55	IC50	280	nM	CHEMBL5400910
6.54	IC50	290	nM	CHEMBL5437136
6.50	IC50	320	nM	CHEMBL5421217
6.36	IC50	440	nM	CHEMBL5412764
6.35	IC50	450	nM	CHEMBL5403412
6.30	IC50	500	nM	CHEMBL5092219
6.30	IC50	500	nM	CHEMBL5083472
6.30	IC50	500	nM	CHEMBL5084401
6.30	IC50	500	nM	CHEMBL5094385
6.30	IC50	500	nM	CHEMBL5080439
6.30	IC50	500	nM	CHEMBL5087762
6.30	IC50	500	nM	CHEMBL5089604
6.30	IC50	500	nM	CHEMBL5086698
6.30	IC50	500	nM	CHEMBL5073032
6.30	IC50	500	nM	CHEMBL5074955
6.30	IC50	500	nM	CHEMBL5078256
6.30	IC50	500	nM	CHEMBL5084536
6.30	IC50	500	nM	CHEMBL5079191
6.30	IC50	500	nM	CHEMBL5071270
6.30	IC50	500	nM	CHEMBL5086699
6.30	IC50	500	nM	CHEMBL5092836
6.30	IC50	500	nM	CHEMBL5080532
6.30	IC50	500	nM	CHEMBL5085024
6.30	IC50	500	nM	CHEMBL5084246
6.30	IC50	500	nM	CHEMBL5079208
6.30	IC50	500	nM	CHEMBL5092530
6.30	IC50	500	nM	CHEMBL5091123
6.30	IC50	500	nM	CHEMBL5084479
6.30	IC50	500	nM	CHEMBL5082843
6.30	IC50	500	nM	CHEMBL5088608
6.30	IC50	500	nM	CHEMBL5086483
6.30	IC50	500	nM	CHEMBL5075341
6.30	IC50	500	nM	CHEMBL5092121
6.30	IC50	500	nM	CHEMBL5086611
6.30	IC50	500	nM	CHEMBL5077649

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 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
2-phenylbenzo[f][1,3]benzoxazole-4,9-dione	2080127: Inhibition of C-terminal 6-His tagged USP19 (unknown origin) (1 to 1290 residues) using Ub-Rh110MP as substrate by fluorescence based assay	ic50	0.5440	uM
2-(4-fluorophenyl)benzo[f][1,3]benzoxazole-4,9-dione	2080127: Inhibition of C-terminal 6-His tagged USP19 (unknown origin) (1 to 1290 residues) using Ub-Rh110MP as substrate by fluorescence based assay	ic50	0.8800	uM

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Ozone	affects cotreatment, decreases expression, increases oxidation, increases expression, increases abundance (+1 more)	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases expression, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases expression, increases abundance	2
Air Pollutants	decreases expression, increases abundance, increases oxidation, affects expression, affects cotreatment	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gallic Acid	decreases expression, increases expression	1
Ivermectin	decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
2,4-Dichlorophenoxyacetic Acid	increases expression	1
Cadmium Chloride	decreases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression, increases oxidation	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4372593	Binding	Inhibition of USP19 in HEK293T cell lysates at 25 uM using HA-tagged vinyl-sulfone as substrate preincubated for 19 to 60 mins followed by substrate addition and measured after 19 to 25 mins by Western blot analysis	Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor. — Bioorg Med Chem Lett

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C0KL	AIW002-02/USP19-KO	Induced pluripotent stem cell	Male
CVCL_KU18	HeLa SilenciX USP19	Cancer cell line	Female
CVCL_TW68	HAP1 USP19 (-) 1	Cancer cell line	Male
CVCL_TW69	HAP1 USP19 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea