| 2020 |
JOSD2 directly interacts with and deubiquitinates a metabolic enzyme complex comprising Aldolase A, Phosphofructokinase-1, and Phosphoglycerate dehydrogenase, stabilizing these enzymes and enhancing their activities and the glycolytic rate; a catalytically inactive JOSD2 mutant fails to deubiquitinate or stabilize this complex, demonstrating activity dependence. |
In vitro and in vivo deubiquitination assays, catalytically inactive mutant analysis, enzyme activity assays, co-immunoprecipitation |
Cell death and differentiation |
High |
33082514
|
| 2021 |
JOSD2 deubiquitinates YAP and TAZ, cleaving their polyubiquitin chains in a deubiquitinase activity-dependent manner, thereby preventing their proteasomal degradation and sustaining their protein levels in cholangiocarcinoma cells. |
Deubiquitination assays, proteasome inhibitor rescue, JOSD2 knockdown/depletion with YAP/TAZ protein level measurement, in vitro and in vivo proliferation assays |
Acta pharmaceutica Sinica. B |
Medium |
35024322
|
| 2022 |
JOSD2 interacts with PKM2 (identified by mass spectrometry and co-immunoprecipitation) and inhibits PKM2 nuclear localization by reducing its K433 acetylation modification, without affecting PKM2 protein stability. |
Mass spectrometry, co-immunoprecipitation, co-immunofluorescence, acetylation assays, nuclear/cytoplasmic fractionation |
Experimental hematology & oncology |
Medium |
35836282
|
| 2022 |
JOSD2 binds to CTNNB1 (beta-catenin) and reduces its ubiquitination level, thereby stabilizing CTNNB1 and augmenting Wnt signaling pathway transduction in hepatocellular carcinoma cells. |
Co-immunoprecipitation, ubiquitination assays, Wnt pathway reporter assays, rescue experiments |
Cell biology international |
Medium |
35568970
|
| 2023 |
JOSD2 interacts with SERCA2a (sarco/endoplasmic reticulum calcium ATPase 2a) and mediates its deubiquitination, enhancing SERCA2a stability; JOSD2 deficiency impairs calcium handling and promotes hypertrophy in primary cardiomyocytes. |
Proteome-wide quantitative analysis (mass spectrometry), co-immunoprecipitation, deubiquitination assays, JOSD2 knockout mice, AAV9-mediated cardiac overexpression, calcium handling assays |
Nature cardiovascular research |
High |
39195964
|
| 2023 |
DNA damaging agents increase nuclear localization of JOSD2, and JOSD2 overexpression promotes DNA damage repair (DDR) pathway activation in NSCLC cells; JOSD2 depletion enhances sensitivity to DNA damaging agents. |
Immunofluorescence (nuclear localization), Western blotting (DDR pathway proteins), sulforhodamine B cytotoxicity assay, gene set enrichment analysis |
Journal of Zhejiang University. Medical sciences |
Low |
37899394
|
| 2024 |
JOSD2 restricts the kinase activity of LKB1 by removing K6-linked polyubiquitination from LKB1, an action vital for maintaining integrity of the LKB1-STRAD-MO25 complex, thereby suppressing LKB1 tumor suppressor function in NSCLC. |
Co-immunoprecipitation, ubiquitination assays (K6-linked chain specificity), kinase activity assays, in vivo xenograft models |
Signal transduction and targeted therapy |
Medium |
38177135
|
| 2024 |
JOSD2 interacts with CaMKIIδ and directly hydrolyzes K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing CaMKIIδ phosphorylation and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes; these effects are reversed by the CaMKIIδ inhibitor KN-93. |
Mass spectrometry, co-immunoprecipitation, deubiquitination assays (K63-chain specific), phosphorylation assays, in vivo cardiac remodeling models, pharmacological inhibition rescue |
Cellular and molecular life sciences : CMLS |
High |
38195959
|
| 2024 |
JOSD2 binds to the C-terminal of IMPDH2 and preferentially cleaves K63-linked polyubiquitin chains at the K134 site of IMPDH2, suppressing IMPDH2 activity and preventing NF-κB activation and inflammation in macrophages. |
Co-immunoprecipitation, ubiquitination assays (K63-linked, K134 site-specific), IMPDH2 enzyme activity assays, NF-κB reporter assays, myeloid-specific JOSD2 knockout mice, bone marrow transplantation, AAV6-mediated overexpression |
Acta pharmaceutica Sinica. B |
High |
40177575
|
| 2024 |
JOSD2 interacts with SMAD7 at its MH1 domain and removes K48-linked ubiquitin chains from SMAD7 at lysine 220, sustaining SMAD7 stability and inhibiting TGFβ-SMAD pathway-driven vascular remodeling. |
LC-MS/MS, co-immunoprecipitation, ubiquitination assays (K48-chain and K220 site-specific), domain mapping, JOSD2 KO mice, VSMC-specific JOSD2 overexpression |
Acta pharmacologica Sinica |
High |
39833306
|
| 2025 |
JOSD2 directly interacts with and stabilizes KRAS mutant variants by removing their proteolytic ubiquitination; reciprocally, KRAS mutants inhibit CHIP (E3 ubiquitin ligase for JOSD2), forming a JOSD2/KRAS positive feedback circuit. Inhibition of JOSD2 promotes polyubiquitination and proteasomal degradation of KRAS mutants. |
DUB siRNA library screen, co-immunoprecipitation, ubiquitination assays, CHIP kinase activity assays, RNA interference, pharmacological JOSD2 inhibitor, patient-derived cells/xenografts/organoids |
Nature communications |
High |
40240366
|
| 2025 |
JOSD2 removes K63-linked ubiquitination from SIRT7 via its active site C24 and promotes P62-mediated autophagic degradation of SIRT7, which prevents phosphorylation and nuclear translocation of P65 (NF-κB) and reduces inflammatory responses in renal tubular epithelial cells. |
Mass spectrometry, co-immunoprecipitation, ubiquitination assays (K63-linked), active site mutagenesis (C24), autophagy flux assays, P65 nuclear translocation assays, JOSD2 KO mice, renal tubular-specific JOSD2 overexpression |
Acta pharmacologica Sinica |
High |
40217118
|
| 2025 |
JOSD2 interacts with and stabilizes SMAD4 by removing polyubiquitin chains, promoting TGF-β signaling and breast cancer metastasis; RNA interference-mediated JOSD2 inhibition reduces breast cancer cell metastasis in vitro and in vivo. |
Co-immunoprecipitation, ubiquitination assays, in vitro migration/invasion assays, in vivo metastasis models |
Biochemical pharmacology |
Medium |
39793716
|
| 2025 |
JOSD2 suppresses cGAS enzymatic activity by removing K27-linked ubiquitination from cGAS, thereby inhibiting the cGAS-STING signaling pathway and promoting M2 macrophage polarization; pharmacological inhibition of JOSD2 reactivates cGAS-STING signaling. |
Co-immunoprecipitation, ubiquitination assays (K27-linked chain specific), cGAS enzymatic activity assays, macrophage polarization assays, pharmacological JOSD2 inhibitor in vitro and in vivo |
Oncoimmunology |
Medium |
41351298
|
| 2025 |
JOSD2 deubiquitinates K63-linked ubiquitin chains on AKT via its active site H125, promoting P62-mediated autophagic degradation of AKT in renal tubular epithelial cells, thereby reducing AKT levels, renal EMT, and fibrosis. |
Mass spectrometry, co-immunoprecipitation, ubiquitination assays (K63-linked), active site mutagenesis (H125), autophagic degradation assays, JOSD2 KO mice, renal tubular-specific JOSD2 overexpression |
Cellular signalling |
High |
41412561
|
| 2025 |
A small-molecule JOSD2 inhibitor (compound 31) bearing a cyanamide warhead covalently engages the catalytic cysteine residue of JOSD2, confirming cysteine-dependent catalytic mechanism; compound 31 induces downregulation of KRAS protein in HCT116 cells. |
High-throughput screening, structure-activity relationship analysis, covalent binding mode characterization, Western blotting for KRAS protein levels |
Bioorganic chemistry |
Medium |
41092805
|