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.
Highlights
Pyroptosis is a form of programmed cell death, characterized by cell swelling, pore formation in the cell membrane, and cell lysis, releasing the cytoplasmic contents [1,2,3,4]
We found that co-expression of HAubiquitin and Flag-human Gasdermin D (GSDMD)-induced ubiquitination of human GSDMD (Fig. 1A)
Given that GSDMD is the key effector of pyroptosis downstream of activated canonical and noncanonical inflammasomes [5, 6], we evaluated the role of GSDMD ubiquitination in pyroptosis
Summary
Pyroptosis is a form of programmed cell death, characterized by cell swelling, pore formation in the cell membrane, and cell lysis, releasing the cytoplasmic contents [1,2,3,4]. It plays an important role in host defense and inflammatory responses [5]. As the final downstream effector of inflammasomes activation, GSDMD is cleaved by inflammatory caspases at the junction between the N-terminal cytotoxic domain (GSDMD-p30) and C-terminal autoinhibitory domain (GSDMD-p20) [5, 13, 14]. GSDMD-p30 binds (cellular) phospholipids and oligomerizes to form 10–20 nm pores on the plasma membrane, triggering pyroptotic cell death [15,16,17,18,19]
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