JOSD1

Summary

JOSD1 (Josephin domain containing 1, HGNC:28953) is a protein-coding gene on chromosome 22q13.1, encoding Josephin-1 (Q15040). Deubiquitinates monoubiquitinated probes (in vitro).

Predicted to enable cysteine-type deubiquitinase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within several processes, including endocytosis; membrane biogenesis; and protein deubiquitination. Located in membrane.

Source: NCBI Gene 9929 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 22 total
• Druggable target: yes
• MANE Select transcript: NM_001360236

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28953
Approved symbol	JOSD1
Name	Josephin domain containing 1
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0063
Ensembl gene	ENSG00000100221
Ensembl biotype	protein_coding
OMIM	615323
Entrez	9929

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000216039, ENST00000412832, ENST00000417712, ENST00000427389, ENST00000456626, ENST00000462610, ENST00000482442, ENST00000490169, ENST00000545590, ENST00000683374, ENST00000866135, ENST00000866136, ENST00000866137, ENST00000866138, ENST00000866139, ENST00000931670

RefSeq mRNA: 3 — MANE Select: NM_001360236 NM_001360235, NM_001360236, NM_014876

CCDS: CCDS13976

Canonical transcript exons

ENST00000683374 — 5 exons

Exon	Start	End
ENSE00000654472	38688935	38689129
ENSE00001122538	38685543	38688001
ENSE00001717255	38699803	38700618
ENSE00001893771	38700800	38700943
ENSE00003787872	38689296	38689424

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 95.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.1575 / max 625.4497, expressed in 1817 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194208	19.8464	1811
194206	7.5630	1726
194209	1.9438	1288
194205	1.2420	733
194210	1.0586	753
194207	0.5091	266
194212	0.4260	108
194211	0.2175	82
194204	0.1859	59
194213	0.1653	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	95.12	gold quality
colonic mucosa	UBERON:0000317	95.09	gold quality
jejunal mucosa	UBERON:0000399	94.20	gold quality
ganglionic eminence	UBERON:0004023	93.76	gold quality
stromal cell of endometrium	CL:0002255	93.75	gold quality
rectum	UBERON:0001052	93.64	gold quality
gall bladder	UBERON:0002110	93.42	gold quality
left ovary	UBERON:0002119	93.17	gold quality
amniotic fluid	UBERON:0000173	93.09	gold quality
islet of Langerhans	UBERON:0000006	92.96	gold quality
right ovary	UBERON:0002118	92.87	gold quality
cortical plate	UBERON:0005343	92.84	gold quality
ovary	UBERON:0000992	92.67	gold quality
mucosa of urinary bladder	UBERON:0001259	92.63	gold quality
ventricular zone	UBERON:0003053	92.48	gold quality
duodenum	UBERON:0002114	92.36	gold quality
cartilage tissue	UBERON:0002418	92.22	gold quality
right lung	UBERON:0002167	92.12	gold quality
left uterine tube	UBERON:0001303	92.03	gold quality
transverse colon	UBERON:0001157	91.86	gold quality
popliteal artery	UBERON:0002250	91.67	gold quality
tibial artery	UBERON:0007610	91.67	gold quality
large intestine	UBERON:0000059	91.48	gold quality
right frontal lobe	UBERON:0002810	91.47	gold quality
colon	UBERON:0001155	91.40	gold quality
omental fat pad	UBERON:0010414	91.37	gold quality
peritoneum	UBERON:0002358	91.36	gold quality
artery	UBERON:0001637	91.33	gold quality
intestine	UBERON:0000160	91.31	gold quality
aorta	UBERON:0000947	91.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-110499	no	506.95
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

119 targeting JOSD1, 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-6740-5P	100.00	65.64	932
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-613	99.91	71.50	1710

Literature-anchored findings (GeneRIF, showing 3)

• The gain of function studies indicated that Josephin domain containing 1 activate NR5A1 gene expression. (PMID:18579725)
• In this study, the authors report that JOSD1 plays an important role in regulating type-I interferon (IFN-I)-mediated antiviral activity. JOSD1 physically interacts with SOCS1, which is an essential negative regulator of many cytokines signaling, and enhances SOCS1 stability by deubiquitinating K48-linked polyubiquitination of SOCS1. (PMID:28355105)
• JOSD1 inhibits mitochondrial apoptotic signalling to drive acquired chemoresistance in gynaecological cancer by stabilizing MCL1. (PMID:31043700)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	josd1	ENSDARG00000071548
mus_musculus	Josd1	ENSMUSG00000022426
rattus_norvegicus	Josd1	ENSRNOG00000014440
drosophila_melanogaster	Josd	FBGN0029853
caenorhabditis_elegans		WBGENE00022190

Paralogs (1): JOSD2 (ENSG00000161677)

Protein

Protein identifiers

Josephin-1 — Q15040 (reviewed: Q15040)

Alternative names: Josephin domain-containing protein 1

All UniProt accessions (6): Q15040, B0QY55, B0QY56, B0QY57, B0QY58, H0YGT9

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinates monoubiquitinated probes (in vitro). When ubiquitinated, cleaves ‘Lys-63’-linked and ‘Lys-48’-linked poly-ubiquitin chains (in vitro), hence may act as a deubiquitinating enzyme. May increase macropinocytosis and suppress clathrin- and caveolae-mediated endocytosis. May enhance membrane dynamics and cell motility independently of its catalytic activity.

Subunit / interactions. Interacts with beta-actin/ACTB.

Subcellular location. Cell membrane. Cytoplasm.

Post-translational modifications. Monoubiquitinated. Ubiquitination activates deubiquitination activity in vitro.

RefSeq proteins (3): NP_001347164, NP_001347165, NP_055691 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006155	Josephin	Domain
IPR040053	JOSD1/2	Family

Pfam: PF02099

UniProt features (7 total): active site 2, chain 1, domain 1, modified residue 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15040-F1	85.54	0.66

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): 36 (nucleophile); 139 (proton acceptor)

Post-translational modifications (1): 15

Mutagenesis-validated functional residues (1):

Position	Phenotype
36	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: 202 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GAANYNYGACNY_UNKNOWN, GOBP_MEMBRANE_BIOGENESIS, AAGCCAT_MIR135A_MIR135B, HSIAO_HOUSEKEEPING_GENES, CREBP1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, CACCAGC_MIR138, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, PAX2_01, CREB_Q4, CATTTCA_MIR203, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, HEN1_01

GO Biological Process (6): proteolysis (GO:0006508), endocytosis (GO:0006897), protein deubiquitination (GO:0016579), membrane biogenesis (GO:0044091), cell motility (GO:0048870), membrane organization (GO:0061024)

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 (4): cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), 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	3
protein metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
cellular component biogenesis	1
cellular process	1
cellular component organization	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
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1130 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
JOSD1	ATXN3	P54252	954
JOSD1	ATXN3L	Q9H3M9	861
JOSD1	UCHL3	P15374	821
JOSD1	COPS5	Q92905	807
JOSD1	USP1	O94782	793
JOSD1	RAD23B	P54727	759
JOSD1	ZUP1	Q96AP4	735
JOSD1	VCP	P55072	703
JOSD1	RAD23A	P54725	653
JOSD1	SLC13A5	Q86YT5	643
JOSD1	USP7	Q93009	643
JOSD1	USP14	P54578	639
JOSD1	MPND	Q8N594	638
JOSD1	OTUB1	Q96FW1	622
JOSD1	USP17L2	Q6R6M4	591

IntAct

100 interactions, top by confidence:

A	B	Type	Score
KRTAP10-8	JOSD1	psi-mi:“MI:0915”(physical association)	0.720
KRT40	JOSD1	psi-mi:“MI:0915”(physical association)	0.720
JOSD1	KRTAP9-2	psi-mi:“MI:0915”(physical association)	0.720
JOSD1	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.720
KRTAP9-2	JOSD1	psi-mi:“MI:0915”(physical association)	0.720
JOSD1	KRT40	psi-mi:“MI:0915”(physical association)	0.720
JOSD1	TRIM27	psi-mi:“MI:0915”(physical association)	0.670
TRIM27	JOSD1	psi-mi:“MI:0915”(physical association)	0.670
EIF3F	EIF3CL	psi-mi:“MI:0914”(association)	0.640
	JOSD1	psi-mi:“MI:0915”(physical association)	0.560
JOSD1	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	JOSD1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-4	JOSD1	psi-mi:“MI:0915”(physical association)	0.560
JOSD1	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
JOSD1	KRT31	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	JOSD1	psi-mi:“MI:0915”(physical association)	0.560
MID2	JOSD1	psi-mi:“MI:0915”(physical association)	0.560
JOSD1		psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	JOSD1	psi-mi:“MI:0915”(physical association)	0.560
JOSD1	TRIM23	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (76): JOSD1 (Two-hybrid), JOSD1 (Two-hybrid), JOSD1 (Two-hybrid), JOSD1 (Two-hybrid), JOSD1 (Two-hybrid), MID2 (Two-hybrid), KRTAP9-2 (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-4 (Two-hybrid), KRTAP10-8 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), UBC (Biochemical Activity), JOSD1 (Affinity Capture-MS), JOSD1 (Two-hybrid)

ESM2 similar proteins: A0FKG7, O00763, O04482, O35815, P09936, P15374, P23356, P45974, P50103, P54252, P56399, P58321, Q00981, Q05B57, Q06AB3, Q0IIH8, Q15040, Q1RMU2, Q2TBG8, Q32Q05, Q4R528, Q5BJY4, Q5EAE5, Q5R407, Q5R739, Q5RED8, Q5VVQ6, Q60HC8, Q640G7, Q66H62, Q6DG88, Q6IQS6, Q6SEG5, Q80TQ2, Q80YV4, Q8CI33, Q8GWE1, Q91Y78, Q9CV28, Q9CVD2

Diamond homologs: O82391, Q15040, Q5BJY4, Q5EAE5, Q5R739, Q8TAC2, Q9CR30, Q9DBJ6, Q9W422, Q9M391

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 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
Keratinization	15	33.4×	6e-19
Formation of the cornified envelope	6	21.1×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
intermediate filament organization	5	48.1×	7e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

451 predictions. Top by Δscore:

Variant	Effect	Δscore
22:38687998:CTTC:C	acceptor_gain	1.0000
22:38688929:GATTA:G	donor_loss	1.0000
22:38688930:ATTAC:A	donor_loss	1.0000
22:38688931:TTAC:T	donor_loss	1.0000
22:38688932:TA:T	donor_loss	1.0000
22:38688933:A:AT	donor_loss	1.0000
22:38688934:CCTGA:C	donor_loss	1.0000
22:38689125:CATCC:C	acceptor_gain	1.0000
22:38689127:TCC:T	acceptor_gain	1.0000
22:38689128:CCC:C	acceptor_gain	1.0000
22:38689421:CAAC:C	acceptor_gain	1.0000
22:38689422:AAC:A	acceptor_gain	1.0000
22:38689422:AACC:A	acceptor_loss	1.0000
22:38689423:AC:A	acceptor_gain	1.0000
22:38689423:ACC:A	acceptor_loss	1.0000
22:38689424:CC:C	acceptor_gain	1.0000
22:38689428:CCAA:C	acceptor_gain	1.0000
22:38689429:CAA:C	acceptor_gain	1.0000
22:38689431:A:AC	acceptor_gain	1.0000
22:38689431:A:C	acceptor_gain	1.0000
22:38700400:T:TA	donor_gain	1.0000
22:38688001:CCTA:C	acceptor_gain	0.9900
22:38688003:T:A	acceptor_loss	0.9900
22:38689126:ATCCC:A	acceptor_loss	0.9900
22:38689127:TCCC:T	acceptor_loss	0.9900
22:38689128:CC:C	acceptor_gain	0.9900
22:38689129:CC:C	acceptor_gain	0.9900
22:38689129:CCTGC:C	acceptor_loss	0.9900
22:38689130:C:CC	acceptor_gain	0.9900
22:38689130:C:CG	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000178459 (22:38694671 G>C), RS1000264274 (22:38700393 C>T), RS1000511976 (22:38699494 G>C), RS1000865457 (22:38687643 T>C), RS1001064913 (22:38690357 G>A,T), RS1001617309 (22:38701592 C>T), RS1001717765 (22:38700639 C>G,T), RS1001768451 (22:38700939 C>A,G,T), RS1001867625 (22:38690441 C>G,T), RS1002028446 (22:38696279 C>T), RS1002049949 (22:38701689 G>A,T), RS1002102428 (22:38702009 C>A,G,T), RS1002230205 (22:38692535 T>A,G), RS1002345261 (22:38702965 A>G), RS1002453645 (22:38698222 A>AT)

Disease associations

OMIM: gene MIM:615323 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003818_40	Resting heart rate	5.000000e-16
GCST007561_72	Sleep duration	4.000000e-08
GCST90002400_507	Plateletcrit	4.000000e-09
GCST90013407_53	Liver enzyme levels (gamma-glutamyl transferase)	7.000000e-40

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630825 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	increases expression	1
Arsenic	affects methylation	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	increases phosphorylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	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
CHEMBL4606006	Binding	Inhibition of human His6-tagged JOSD1 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

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2ZI	Abcam HEK293T JOSD1 KO	Transformed cell line	Female
CVCL_ST83	HAP1 JOSD1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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