Lipopolysaccharide reduces USP13 stability through c-Jun N-terminal kinase activation in Kupffer cells.

Abstract

Protein ubiquitination regulates protein stability, cellular localization, and enzyme activity. Deubiquitinases catalyze the removal of ubiquitin from target proteins and reverse ubiquitination. USP13, a deubiquitinase, has been shown to regulate a variety of cellular responses including inflammation; however, the molecular regulation of USP13 has not been demonstrated. In this study, we revealed that USP13 is degraded in response to lipopolysaccharide (LPS) in Kupffer cells. USP13 levels are significantly decreased in inflamed organs, including liver tissues from septic mice. LPS reduces USP13 protein stability, not transcription, in Kupffer cells. Furthermore, LPS increases USP13 polyubiquitination. Inhibition of proteasome, but not lysosome or immunoproteasome, attenuates LPS-induced USP13 degradation, suggesting USP13 degradation is mediated by the ubiquitin-proteasome system. A catalytically inactive form of USP13 exhibits similar degree of degradation compared with USP13 wild-type, suggesting that USP13 degradation is not dependent on its activity. Furthermore, USP13 degradation is dependent on new protein synthesis. Inhibition of c-Jun N-terminal kinase (JNK) attenuates USP13 degradation, indicating that JNK-dependent new protein synthesis is necessary for USP13 degradation. This study reveals a molecular mechanism of regulation of USP13 degradation in Kupffer cells in response to bacterial endotoxin.

• Authors: Fan Yu, Yanhui Li, Qinmao Ye, Jiaxing Miao, Sarah J Taleb, Yutong Zhao, Jing Zhao
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 236 Issue 6 Pg. 4360-4368 (06 2021) ISSN: 1097-4652 [Electronic] United States
• PMID: 33169399 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Lipopolysaccharides
• JNK Mitogen-Activated Protein Kinases
• Ubiquitin-Specific Proteases
• Usp13 protein, mouse
• Proteasome Endopeptidase Complex

Topics

• Animals
• Disease Models, Animal
• Enzyme Activation
• Enzyme Stability
• Hep G2 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Kupffer Cells (enzymology, microbiology, pathology)
• Lipopolysaccharides
• Male
• Mice
• Mice, Inbred C57BL
• Proteasome Endopeptidase Complex (metabolism)
• RAW 264.7 Cells
• Sepsis (chemically induced, enzymology, microbiology, pathology)
• Signal Transduction
• Ubiquitin-Specific Proteases (genetics, metabolism)
• Ubiquitination