JOSD2

Summary

JOSD2 (Josephin domain containing 2, HGNC:28853) is a protein-coding gene on chromosome 19q13.33, encoding Josephin-2 (Q8TAC2). Cleaves ‘Lys-63’-linked poly-ubiquitin chains, and with lesser efficiency ‘Lys-48’-linked poly-ubiquitin chains (in vitro).

This gene encodes a protein containing a Josephin domain. Josephin domain-containing proteins are deubiquitinating enzymes which catalyze the hydrolysis of the bond between the C-terminal glycine of the ubiquitin peptide and protein substrates. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 126119 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 41 total
• Druggable target: yes
• MANE Select transcript: NM_001270639

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28853
Approved symbol	JOSD2
Name	Josephin domain containing 2
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	SBBI54
Ensembl gene	ENSG00000161677
Ensembl biotype	protein_coding
OMIM	615324
Entrez	126119

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 2 retained_intron

ENST00000594350, ENST00000595669, ENST00000595718, ENST00000598418, ENST00000601423, ENST00000602146, ENST00000884030, ENST00000884031, ENST00000884032, ENST00000884033, ENST00000884034, ENST00000884035, ENST00000884036, ENST00000950918, ENST00000950919, ENST00000950920, ENST00000950921

RefSeq mRNA: 5 — MANE Select: NM_001270639 NM_001270639, NM_001270640, NM_001270641, NM_001270686, NM_138334

CCDS: CCDS12797, CCDS59413

Canonical transcript exons

ENST00000598418 — 5 exons

Exon	Start	End
ENSE00001059623	50507574	50507699
ENSE00001059625	50506378	50506572
ENSE00001124496	50510286	50510448
ENSE00003091128	50511117	50511191
ENSE00003902254	50505998	50506272

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 97.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.3761 / max 157.6502, expressed in 1799 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182224	7.6817	1714
182223	7.1798	1654
182222	2.5815	1328
182225	1.9331	1123

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	97.17	gold quality
spinal cord	UBERON:0002240	96.02	gold quality
apex of heart	UBERON:0002098	95.99	gold quality
right lobe of thyroid gland	UBERON:0001119	94.21	gold quality
lower esophagus	UBERON:0013473	94.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.07	gold quality
mucosa of transverse colon	UBERON:0004991	94.04	gold quality
lower esophagus mucosa	UBERON:0035834	94.02	gold quality
putamen	UBERON:0001874	93.89	gold quality
left coronary artery	UBERON:0001626	93.65	gold quality
tibial nerve	UBERON:0001323	93.63	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.56	gold quality
left lobe of thyroid gland	UBERON:0001120	93.43	gold quality
amygdala	UBERON:0001876	93.38	gold quality
stromal cell of endometrium	CL:0002255	93.37	gold quality
body of stomach	UBERON:0001161	93.31	gold quality
coronary artery	UBERON:0001621	93.29	gold quality
granulocyte	CL:0000094	93.11	gold quality
anterior cingulate cortex	UBERON:0009835	93.10	gold quality
hypothalamus	UBERON:0001898	93.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.96	gold quality
ectocervix	UBERON:0012249	92.79	gold quality
ascending aorta	UBERON:0001496	92.77	gold quality
right coronary artery	UBERON:0001625	92.76	gold quality
esophagus	UBERON:0001043	92.75	gold quality
right frontal lobe	UBERON:0002810	92.75	gold quality
thoracic aorta	UBERON:0001515	92.72	gold quality
tendon of biceps brachii	UBERON:0008188	92.72	gold quality
omental fat pad	UBERON:0010414	92.64	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.26
E-CURD-112	no	2.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting JOSD2, 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-6825-5P	99.96	69.81	3431
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-34A-3P	96.80	67.70	805
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-9899	91.24	59.59	90

Literature-anchored findings (GeneRIF, showing 5)

• The deubiquitinase JOSD2 is a positive regulator of glucose metabolism. (PMID:33082514)
• Deubiquitinating enzyme JOSD2 promotes hepatocellular carcinoma progression through interacting with and inhibiting CTNNB1 degradation. (PMID:35568970)
• Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma. (PMID:36583817)
• Deubiquitinating enzyme JOSD2 affects susceptibility of non-small cell lung carcinoma cells to anti-cancer drugs through DNA damage repair. (PMID:37899394)
• Josephin domain containing 2 (JOSD2) promotes lung cancer by inhibiting LKB1 (Liver kinase B1) activity. (PMID:38177135)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	josd2	ENSDARG00000057626
mus_musculus	Josd2	ENSMUSG00000038695
rattus_norvegicus	Josd2	ENSRNOG00000019442
drosophila_melanogaster	Josd	FBGN0029853
caenorhabditis_elegans		WBGENE00022190

Paralogs (1): JOSD1 (ENSG00000100221)

Protein

Protein identifiers

Josephin-2 — Q8TAC2 (reviewed: Q8TAC2)

Alternative names: Josephin domain-containing protein 2

All UniProt accessions (2): Q8TAC2, M0QZL8

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves ‘Lys-63’-linked poly-ubiquitin chains, and with lesser efficiency ‘Lys-48’-linked poly-ubiquitin chains (in vitro). May act as a deubiquitinating enzyme.

Subcellular location. Cytoplasm. Cytosol.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TAC2-1	1	yes
Q8TAC2-2	2

RefSeq proteins (5): NP_001257568, NP_001257569, NP_001257570, NP_001257615, NP_612207 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006155	Josephin	Domain
IPR040053	JOSD1/2	Family

Pfam: PF02099

UniProt features (22 total): strand 7, helix 7, active site 2, turn 2, chain 1, domain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6PGV	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TAC2-F1	90.42	0.74

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): 24 (nucleophile); 125 (proton acceptor)

Mutagenesis-validated functional residues (1):

Position	Phenotype
24	loss of deubiquitination activity, no change in subcellular location.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5689877	Josephin domain DUBs
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 105 (showing top): SP3_Q3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GGGTGGRR_PAX4_03, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GATA1_01, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, CYTAGCAAY_UNKNOWN, PITX2_Q2, AP2GAMMA_01, TTCNRGNNNNTTC_HSF_Q6, CGTSACG_PAX3_B, GOBP_PROTEOLYSIS, RFX1_01, SCGGAAGY_ELK1_02

GO Biological Process (2): proteolysis (GO:0006508), protein deubiquitination (GO:0016579)

GO Molecular Function (5): cysteine-type deubiquitinase activity (GO:0004843), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), deubiquitinase activity (GO:0101005)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deubiquitination	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
ubiquitin-like protein peptidase activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
JOSD2	UCHL3	P15374	829
JOSD2	COPS5	Q92905	790
JOSD2	USP1	O94782	781
JOSD2	RAD23B	P54727	765
JOSD2	ZUP1	Q96AP4	735
JOSD2	VCP	P55072	713
JOSD2	RAD23A	P54725	657
JOSD2	USP7	Q93009	652
JOSD2	MPND	Q8N594	647
JOSD2	SLC13A5	Q86YT5	646
JOSD2	UCHL5	Q9Y5K5	629
JOSD2	OTUB1	Q96FW1	605
JOSD2	YOD1	Q5VVQ6	604
JOSD2	USP14	P54578	586
JOSD2	STAMBP	O95630	585

IntAct

43 interactions, top by confidence:

A	B	Type	Score
AHCYL1	JOSD2	psi-mi:“MI:0915”(physical association)	0.740
JOSD2	AHCYL1	psi-mi:“MI:0914”(association)	0.740
COMMD3	VPS26C	psi-mi:“MI:0914”(association)	0.640
SPRR3	JOSD2	psi-mi:“MI:0915”(physical association)	0.590
MCEMP1	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
JOSD2	TRAPPC2	psi-mi:“MI:0915”(physical association)	0.560
JOSD2	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
YIF1A	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
TRAPPC2	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
JOSD2	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
SYP	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
MDK	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
COQ8A	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
TMEM132E-DT	TXNDC9	psi-mi:“MI:0914”(association)	0.560
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
C2orf68	PIR	psi-mi:“MI:0914”(association)	0.530
ZFP41	LRP4	psi-mi:“MI:0914”(association)	0.530
LRRC51	JOSD2	psi-mi:“MI:0915”(physical association)	0.400
TOMT	JOSD2	psi-mi:“MI:0915”(physical association)	0.400
JOSD2		psi-mi:“MI:0914”(association)	0.350
MCEMP1	GUK1	psi-mi:“MI:0914”(association)	0.350
JOSD2	CMTM5	psi-mi:“MI:0915”(physical association)	0.000
JOSD2	YIF1A	psi-mi:“MI:0915”(physical association)	0.000
JOSD2	FKBP7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (988): PLA2G2A (Biochemical Activity), UBC (Biochemical Activity), AHCYL2 (Affinity Capture-MS), AHCYL1 (Affinity Capture-MS), TRAPPC2 (Affinity Capture-MS), DUSP28 (Affinity Capture-MS), HBB (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), JOSD2 (Affinity Capture-MS), JOSD2 (Affinity Capture-MS), AHCYL2 (Affinity Capture-MS), TRAPPC2 (Affinity Capture-MS), AHCYL1 (Affinity Capture-MS), JOSD2 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4L8, A1A4Q9, A1L134, A2BDX3, A5YM72, A6H707, B0BLZ5, B0JZP3, G3MZR2, O43292, O60831, O89109, P70295, Q11130, Q2TBP5, Q2V8X7, Q32NY4, Q3UPE3, Q4R4E4, Q4R4I9, Q5XIE1, Q5ZIW1, Q66HR0, Q6IQX7, Q6NRK8, Q6P2H8, Q7L1V2, Q80ZW2, Q86VU5, Q8IZ52, Q8N3Y3, Q8NE01, Q8NF37, Q8NI29, Q8TAC2, Q8TCD5, Q8TD43, Q8WUY1, Q92839, Q96DE0

Diamond homologs: O82391, Q15040, Q5BJY4, Q5EAE5, Q5R739, Q8TAC2, Q9CR30, Q9DBJ6, Q9W422, Q9M391, O17850, O35815, P54252, Q60XN1, Q8LQ36, Q9CVD2, Q9H3M9, Q9W689

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1338 predictions. Top by Δscore:

Variant	Effect	Δscore
19:50506271:CC:C	acceptor_gain	1.0000
19:50506272:CC:C	acceptor_gain	1.0000
19:50506372:GCTCA:G	donor_loss	1.0000
19:50506373:CTCAC:C	donor_loss	1.0000
19:50506374:TCACC:T	donor_loss	1.0000
19:50506375:CA:C	donor_loss	1.0000
19:50506376:A:AC	donor_gain	1.0000
19:50506377:C:CA	donor_loss	1.0000
19:50506377:C:CC	donor_gain	1.0000
19:50506377:CCTGA:C	donor_gain	1.0000
19:50506568:GGGGC:G	acceptor_gain	1.0000
19:50506569:GGGC:G	acceptor_gain	1.0000
19:50506570:GGC:G	acceptor_gain	1.0000
19:50506571:GC:G	acceptor_gain	1.0000
19:50506572:CC:C	acceptor_gain	1.0000
19:50506573:C:CC	acceptor_gain	1.0000
19:50506574:T:C	acceptor_loss	1.0000
19:50506575:G:C	acceptor_gain	1.0000
19:50507575:T:TA	donor_gain	1.0000
19:50510287:T:TA	donor_gain	1.0000
19:50510310:T:TA	donor_gain	1.0000
19:50512579:CT:C	acceptor_gain	1.0000
19:50512674:G:C	donor_gain	1.0000
19:50512687:T:A	donor_gain	1.0000
19:50512806:CCCAC:C	acceptor_gain	1.0000
19:50512807:CCAC:C	acceptor_gain	1.0000
19:50512807:CCACC:C	acceptor_gain	1.0000
19:50512808:CACC:C	acceptor_gain	1.0000
19:50512810:CCTGG:C	acceptor_loss	1.0000
19:50512811:C:CA	acceptor_loss	1.0000

AlphaMissense

1176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:50506467:C:A	W126C	0.999
19:50506467:C:G	W126C	0.999
19:50507640:T:A	D69V	0.999
19:50506469:A:G	W126R	0.998
19:50506469:A:T	W126R	0.998
19:50506472:G:C	H125D	0.998
19:50506531:A:T	I105N	0.998
19:50507633:A:C	N71K	0.998
19:50507633:A:T	N71K	0.998
19:50507649:C:A	G66V	0.998
19:50507671:G:C	H59D	0.998
19:50510346:A:T	L29H	0.998
19:50506423:G:A	S141F	0.997
19:50506470:G:C	H125Q	0.997
19:50506470:G:T	H125Q	0.997
19:50506531:A:G	I105T	0.997
19:50506537:C:T	G103E	0.997
19:50507590:A:G	W86R	0.997
19:50507590:A:T	W86R	0.997
19:50507640:T:G	D69A	0.997
19:50507644:A:C	Y68D	0.997
19:50507649:C:T	G66D	0.997
19:50507697:A:G	L50S	0.997
19:50510339:G:C	N31K	0.997
19:50510339:G:T	N31K	0.997
19:50510343:T:A	N30I	0.997
19:50510386:G:C	H16D	0.997
19:50506429:A:G	L139P	0.996
19:50506462:G:T	A128D	0.996
19:50506468:C:G	W126S	0.996

dbSNP variants (sampled 300 via entrez): RS1000272945 (19:50508932 A>AGG), RS1000322633 (19:50509938 A>G), RS1000389631 (19:50510211 G>A,C,T), RS1000767299 (19:50512896 G>A), RS1000878326 (19:50507656 C>T), RS1001867876 (19:50509378 C>G), RS1001951441 (19:50506572 C>T), RS1002277908 (19:50509697 G>T), RS1002821748 (19:50510844 A>C), RS1002917038 (19:50508090 C>G,T), RS1003606094 (19:50509840 T>G), RS1003701649 (19:50512041 A>C), RS1003797156 (19:50509462 C>T), RS1004252162 (19:50510361 C>A), RS1004283279 (19:50510566 A>T)

Disease associations

OMIM: gene MIM:615324 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630845 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	4
Arsenic	increases abundance, increases expression, affects cotreatment, decreases expression	2
Valproic Acid	increases expression, increases methylation	2
perfluorooctanoic acid	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
Zinc	increases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4606007	Binding	Inhibition of human 6His-tagged JOSD2 expressed in Escherichia coli assessed as cleavage of Ubiquitin-Rhodamine110-glycine to Ubiquitin and Rhodamine110-glycine using Ubiquitin-Rhodamine110-glycine as substrate by fluorescence based analysi	Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_ST84	HAP1 JOSD2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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