Scutellarin inhibits pyroptosis via selective autophagy degradation of p30/GSDMD and suppression of ASC oligomerization
Danyue Li, Weilv Xu, Suhui He, Xinyue Li, Yumeng Wang, Qian Lv, Nan Chen, Lu Dong, Feng Guo, Fushan Shi
Abstract
Most of the pyroptosis inhibitors targeted Gasdermin D (GSDMD) are functioning by restraining GSDMD-N (p30) oligomerization. For the first time, this work discovered a pyroptosis inhibitor taking effect by degrading p30 and GSDMD. As the principal bioactive constituent in Erigeron breviscapus , scutellarin (SCU) assumes a pivotal role in the realm of anti-inflammatory processes. In this study, SCU demonstrated efficacy in hindering pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome, absent in melanoma 2 (AIM2) inflammasome, NLR-family CARD-containing protein 4 (NLRC4) inflammasome, and that activated through the non-canonical pathway. The inhibitory effect is achieved by thwarting apoptosis-associated speck-like protein containing CARD (ASC) oligomerization and inducing the ubiquitin-dependent selective autophagy of p30/GSDMD. Throughout the autophagic process, SCU facilitates selective autophagy of the pyroptosis executor p30/GSDMD through K33-linked polyubiquitination at Lys51 catalyzed by the E3 ligase tripartite motif-containing 21 (TRIM21). This process contributes to the recognition of p30/GSDMD by the cargo receptor sequestosome 1 (SQSTM1)/p62. The characteristic positions SCU as a prospective clinical intervention for a broader spectrum of inflammatory-related disorders. • SCU inhibits pyroptosis stimulated via multiple pathways. • SCU inhibits pyroptosis through abrogating ASC oligomerization and facilitating the degradation p30/GSDMD. • SCU preferentially targets p30 for degradation over GSDMD under co-existing conditions. • SCU degrades p30/GSDMD through ubiquitin-dependent autophagic machanism. • E3 ligase TRIM21 plays an important role in the degradation induced by SCU.