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

• Published in: Cell death & disease Vol. 13; no. 2; p. 106
• Main Authors: Shi, Yuhua, Yang, Yang, Xu, Weilv, Shi, Dongyun, Xu, Wei, Fu, Xinyu, Lv, Qian, Xia, Jie, Shi, Fushan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.02.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 42; 42/109; 42/89; 45; 45/77; 59; 631/250/1932; 631/250/1933; 64; 82; 82/1; 82/80; 96; 96/63; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Disease; Hypotheses; Immunology; Inflammasomes; Inflammasomes - metabolism; Inflammatory diseases; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Laboratories; Life Sciences; Phosphate-Binding Proteins - metabolism; Pyroptosis; Pyroptosis - physiology; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Veterinary medicine
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04553-x

Gasdermin D (GSDMD) participates in the activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory 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 deficiency 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.