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

Abstract

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.

Synoviolin alleviates GSDMD‐mediated periodontitis by suppressing its stability

“…Until now, the E3 ligases involved in the ubiquitination of GSDMD are not fully elucidated yet. The study by Shi and colleagues described that E3 ligase Synoviolin directly interacted with GSDMD and mediated K27‐linked polyubiquitination of GSDMD, which promoted GSDMD‐induced pyroptosis 36 . In the present study, we also confirmed the interaction between Synoviolin and GSDMD.…”

“…In addition, the ubiquitination of GSDMD in PBMCs isolated from patients with severe periodontitis was further decreased. The E3 ligase Synoviolin has been shown to interact with GSDMD 36 . We co‐transfected plasmid‐encoding Flag‐tagged Synoviolin with plasmid‐encoding GSDMD to HEK293T cells and confirmed the interaction of Synoviolin and GSDMD by immunoprecipitation (Figure 2B).…”

“…A recent study by Shi et al. described that Synoviolin directly interacted with GSDMD, mediated K27‐linked polyubiquitination of GSDMD, and promoted GSDMD‐induced pyroptosis in HEK293T cells 36 . Until now, the precise roles of Synoviolin in periodontitis have never been described.…”

“…35 A recent study by Shi et al described that Synoviolin directly interacted with GSDMD, mediated K27-linked polyubiquitination of GSDMD, and promoted GSDMD-induced pyroptosis in HEK293T cells. 36 Until now, the precise roles of Synoviolin in periodontitis have never been described. Since GSDMD and pyroptosis are involved in periodontitis, we hypothesized that Synoviolin might regulate GSDMD and pyroptosis in periodontitis by ubiquitinating GDDMD and promoting its degradation.…”

Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

“…PhosphositePlus has reported several potential lysine residues ubiquitylated in GSDMD ( Wagner et al, 2011 ; Udeshi et al, 2013 ) ( Table 2 ). Two of these sites Lys203 and Lys204 has been reported to be ubiquitylated by SYVN1, an E3-ligase that mediates K27 polyubiquitylation of GSDMD and promotes its activation ( Shi et al, 2022 ).…”