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Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry
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USP9X regulates copper-induced CASP9/CASP3/GSDME-dependent pyroptosis by deubiquitinating JAK1
Huaduan Zi1,2,3,4, Hengcheng Tang1,2,3, Xiaoxi Yang1,5
1Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Summary
Copper overload in Wilson disease triggers pyroptosis, a form of cell death, by activating the USP9X/JAK1 pathway. Inhibiting this pathway alleviates liver injury, suggesting a new therapeutic target.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Death Research
Background:
- Wilson disease (WD) involves hepatic copper accumulation, but molecular mechanisms of liver injury are unclear.
- Understanding cell death pathways in WD is crucial for developing effective treatments.
Purpose of the Study:
- Investigate if copper overload induces pyroptosis in Wilson disease.
- Elucidate the role of USP9X-mediated JAK1 deubiquitination in copper-induced pyroptosis.
Main Methods:
- Integrated omics analyses (transcriptomics, proteomics, ubiquitinomics) on WD patient liver tissues and cell models.
- Investigated JAK1/STAT1 pathway, CASP9/CASP3/GSDME axis, and USP9X using pharmacological and genetic tools.
- Validated findings in Atp7b knockout mouse models.
Main Results:
- Copper overload activated JAK1/STAT1 signaling, increased ROS, and triggered pyroptosis via CASP9/CASP3/GSDME.
- USP9X upregulated by copper, deubiquitinating and stabilizing JAK1, enhancing downstream signaling.
- Inhibiting JAK1/STAT1 or GSDME attenuated pyroptosis and liver injury in WD models.
Conclusions:
- USP9X deubiquitinates JAK1, promoting pyroptosis and liver injury in Wilson disease.
- Targeting the USP9X/JAK1 axis offers a potential therapeutic strategy for Wilson disease.
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