Deubiquitinase JOSD1 tempers hepatic proteotoxicity.

Area of Science:

• Biochemistry
• Cell Biology
• Hepatology

Background:

• Proteotoxicity, arising from protein homeostasis disruption, is central to liver injury.
• Proteasomal dysfunction and inhibitors contribute to hepatic proteotoxicity.
• Identifying enzymes that reverse proteotoxic damage is crucial for therapeutic development.

Purpose of the Study:

• To screen for deubiquitinating enzymes (DUBs) that counteract proteasomal inhibitor-induced hepatocellular damage.
• To investigate the role and mechanism of JOSD1 in mitigating liver cell proteotoxicity.

Main Methods:

• Conducted a siRNA screen of 96 DUBs in HepG2 cells under proteasomal stress.
• Validated JOSD1's function using gain and loss of function studies in primary mouse hepatocytes.
• Investigated JOSD1's interaction with SOCS1 and its localization under proteotoxic conditions.
• Assessed JOSD1's in vivo effect on liver injury in mice challenged with Bortezomib.

Main Results:

• JOSD1 knockdown increased apoptosis and decreased viability, while its overexpression protected cells.
• JOSD1's protective role requires its monoubiquitination and plasma membrane accumulation.
• JOSD1 deubiquitinates and stabilizes SOCS1, which is essential for its hepatoprotective effects.
• JOSD1 overexpression protected mice from Bortezomib-induced liver injury, while depletion aggravated it.

Conclusions:

• JOSD1 mitigates hepatocellular proteotoxicity by stabilizing SOCS1.
• JOSD1 is a key regulator of liver cell survival under proteotoxic stress.
• JOSD1 represents a promising therapeutic candidate for treating liver diseases characterized by proteotoxicity.