Presenting Author: Tao Yu
, Research Associate at Howard Hughes Med. Inst., Cornell Univ.
Abstract:
Macrophages could response to pathogen and damage-associated molecular patterns through NLRP3-mediated inflammasome. Hyperactivation of NLRP3 is associated with human chronic inflammatory diseases. Therefore, accurate regulation of NLRP3 activation is important. Recent works show that NLRP3 is localized on trans-Golgi network (TGN), which is crucial for NLRP3 activation and consequently ASC recruitment. However, what regulates NLRP3 TGN localization is unknown. Here, we demonstrated that NLRP3 is palmitoylated on Cys126 by palmitoyl-acyltransferase ZDHHC7 in macrophages, which promotes resting NLRP3 localization to TGN and activated NLRP3 localization on dispersed TGN. As a result, ZDHHC7-mediated NLRP3 Cys126 palmitoylation is critical for recruitment and oligomerization of ASC after NLRP3 activation. Perturbating NLRP3 palmitoylation by ZDHHC7 knockout, pharmaceutically inhibition, or modification site mutation, will diminish NLRP3 activation and consequential Caspase-1/GSDMD cleavage, and cytokines secretion in macrophages. Furthermore, NLRP3 palmitoylation on Cys126 is vital for inflammasome activation in vivo, including endotoxic shock and peritonitis mouse models. Notably, this palmitoylation-regulated NLRP3 activation also contributes to multiple sclerosis development in mice. Therefore, our study provides new insight into NLRP3 regulation and suggests targeting ZDHHC7 or NLRP3 Cys126 could be a potential therapeutic strategy to treat human NLRP3-related disorders.
NLRP3 Cys126 palmitoylation by ZDHHC7 Promotes Inflammasome Activation
Category
Poster and Podium (Block Symposium)
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Date: May 6 Presentation Time: 11:30 AM to 12:45 PM Room: Exhibit Hall F1