JOSD1

JOSD1 is an MJD-family cysteine deubiquitinase that serves as a broad stabilizer of substrate proteins by removing K48-linked polyubiquitin chains and protecting its targets from proteasomal degradation (PMID:23625928, PMID:31043700). Its catalytic activity is conditionally switched on: unmodified JOSD1 is inert in vitro, but monoubiquitination of the enzyme licenses ubiquitin-chain cleavage and drives its accumulation at the plasma membrane, where it remodels membrane dynamics and endocytic trafficking (PMID:23625928). The catalytic cysteine is required for both function and proper localization, as the C36A active-site mutant is instead polyubiquitinated, fails to reach the membrane, and is non-functional (PMID:39284830). Through this deubiquitinase activity JOSD1 stabilizes a diverse set of substrates to govern distinct cellular programs: it stabilizes MCL1 to suppress mitochondrial apoptosis and drive chemoresistance (PMID:31043700), stabilizes SOCS1 to restrain type-I interferon signaling and the antiviral response (PMID:28355105, PMID:36069544), and stabilizes the oncogenic mutant kinase JAK2-V617F while sparing wild-type JAK2 (PMID:34326465). In cancer contexts it additionally stabilizes EMT and invasion drivers Snail and Twist1 (PMID:35693075, PMID:41952254) and reinforces Hippo/YAP, Wnt/β-catenin, and Hedgehog-pathway components YAP, SULF1, and SUFU (PMID:39143074, PMID:42140034, PMID:42248831). Beyond degradation control, JOSD1 deubiquitinates PGAM1 at K251 to enable its lactylation, enhancing glycolytic enzyme activity and immune suppression (PMID:42049490), and counteracts hepatic proteotoxicity in a monoubiquitination- and SOCS1-dependent manner (PMID:39284830).

1. 2013 High

   Established that JOSD1 is a deubiquitinase with an unusual activation requirement, answering how this enzyme is regulated: it is catalytically silent until monoubiquitinated.

   Evidence In vitro ubiquitin-chain cleavage assays comparing unmodified versus monoubiquitinated JosD1, plus cell-based localization and time-lapse imaging

   PMID:23625928

   Open questions at the time

   • Identity of the E3 ligase that monoubiquitinates JOSD1 not defined
   • Structural basis of allosteric activation by monoubiquitination not resolved
   • Physiological linkage chains cleaved in cells not fully enumerated
2. 2013 Medium

   Linked JOSD1's activation state to its subcellular address and cellular phenotype, showing monoubiquitination drives membrane localization and alters membrane dynamics and endocytosis.

   Evidence Subcellular fractionation and imaging in mouse tissues and cultured cells, with macropinocytosis and clathrin/caveolae uptake assays under JosD1 gain-of-function

   PMID:23625928

   Open questions at the time

   • Membrane substrates underlying altered trafficking not identified
   • Mechanism coupling membrane localization to endocytic remodeling unknown
3. 2017 Medium

   First defined a specific substrate and pathway, showing JOSD1 stabilizes SOCS1 by removing K48 chains to suppress type-I interferon signaling.

   Evidence Reciprocal Co-IP, K48-linked deubiquitination assay, SOCS1 stability assay, and IFN-I functional readouts

   PMID:28355105

   Open questions at the time

   • Whether JOSD1 monoubiquitination is required for SOCS1 deubiquitination not tested here
   • Single-lab observation
4. 2019 High

   Connected JOSD1 to apoptosis control and therapy resistance by identifying MCL1 as a stabilized substrate.

   Evidence In vivo/in vitro ubiquitination assays, JOSD1 depletion driving MCL1 loss and apoptosis, and a chemoresistant xenograft model

   PMID:31043700

   Open questions at the time

   • Direct binding interface with MCL1 not mapped
   • Generality across non-gynaecological tumors not established
5. 2021 High

   Demonstrated mutant-selective substrate control, showing JOSD1 stabilizes oncogenic JAK2-V617F while sparing the wild-type kinase, defining a therapeutic vulnerability.

   Evidence Chemical genetics screen, Co-IP, ubiquitination assay, cycloheximide chase, and genetic inactivation with primary AML cell viability readout

   PMID:34326465

   Open questions at the time

   • Structural basis for selective recognition of the V617F mutant unknown
   • No defined small-molecule inhibitor characterized
6. 2022 Medium

   Extended JOSD1's role to EMT and viral immune evasion, stabilizing Snail to promote invasion and stabilizing SOCS1 via its SH2 domain to drive IRF7 degradation.

   Evidence Co-IP (including SOCS1 SH2-domain mapping), ubiquitination assays, stability and rescue experiments in tumor cells and during duck Tembusu virus infection

   PMID:35693075 PMID:36069544

   Open questions at the time

   • Direct linkage between JOSD1 membrane localization and these cytoplasmic substrates unaddressed
   • Single-lab findings per substrate
7. 2024 High

   Tied catalytic activity, monoubiquitination, and membrane localization together in vivo and identified a protective physiological role, showing JOSD1 mitigates hepatic proteotoxicity through SOCS1 stabilization.

   Evidence siRNA DUB screen, C36A catalytic mutant, membrane fractionation, Co-IP, ubiquitination assay, and adenoviral in vivo expression/depletion with Bortezomib challenge in mouse hepatocytes

   PMID:39284830

   Open questions at the time

   • How proteotoxic stress triggers JOSD1 monoubiquitination not defined
   • Downstream effectors of SOCS1 in hepatoprotection not fully mapped
8. 2024 Medium

   Revealed a feed-forward circuit by which JOSD1 stabilizes YAP while YAP transcriptionally induces JOSD1, amplifying Hippo/YAP output in colon cancer.

   Evidence shRNA knockdown with tumorigenesis readout, K48-linked ubiquitination assay on YAP, and ChIP showing YAP occupancy at the JOSD1 promoter

   PMID:39143074

   Open questions at the time

   • Whether the feedback loop operates in non-colon tissues unknown
   • Quantitative contribution of the loop to YAP activity not defined
9. 2026 High

   Broadened JOSD1's mechanistic repertoire beyond degradation control to PTM crosstalk, showing site-specific deubiquitination of PGAM1 K251 enables its lactylation and metabolic/immunosuppressive reprogramming.

   Evidence Multi-omics, Co-IP, ubiquitination assay, K251 site-specific mutagenesis, metabolic flux and immune assays, and animal models with liver-targeted JOSD1 inhibition plus anti-PD-1

   PMID:42049490

   Open questions at the time

   • Mechanism by which deubiquitination permits lactylation at the same residue not fully resolved
   • Role of AARS1 partnership in directing JOSD1 not detailed
10. 2026 Medium

    Generalized JOSD1 as a pan-cancer stabilizer of invasion and developmental-pathway regulators, identifying Twist1, SULF1, and SUFU as additional substrates linking it to EMT, Wnt/β-catenin, and Hedgehog-pathway components.

    Evidence Co-IP, deubiquitination assays, cycloheximide chase, and in vivo xenografts with substrate re-expression rescue in glioblastoma, gastric, and pancreatic cancer models

    PMID:41952254 PMID:42140034 PMID:42248831

    Open questions at the time

    • Determinants of JOSD1 substrate selectivity across these diverse targets unknown
    • Whether monoubiquitination/membrane localization gates these interactions untested
    • Single-lab studies per substrate

• It remains unknown what determines JOSD1's broad substrate selectivity and how its monoubiquitination-dependent activation and membrane localization are coordinated with recognition of its many cytoplasmic and nuclear substrates.
• No structural model of substrate engagement
• E3 ligase and signals controlling JOSD1 monoubiquitination not identified
• Relationship between membrane localization and substrate stabilization not mechanistically unified