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E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

By Yuhua Shi, Yang Yang, Weilv Xu, Wei Xu, Xinyu Fu, Qian Lv, Jie Xia, Fushan Shi

Posted 21 Jul 2021
bioRxiv DOI: 10.1101/2021.07.21.453219

Gasdermin D (GSDMD) participates in activation of in[fl]ammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates in[fl]ammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 de[fi]ciency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.

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