NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation.

Abstract

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate-induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

• Authors: Xueqin Jiang, Xinlu Zhang, Xiaoying Cai, Na Li, Hongyu Zheng, Minghai Tang, Jiangli Zhu, Kaiyue Su, Ruijia Zhang, Neng Ye, Jing Peng, Min Zhao, Wenshuang Wu, Jianhong Yang, Haoyu Ye
• Journal: Science advances (Sci Adv) Vol. 10 Issue 6 Pg. eadi9284 (Feb 09 2024) ISSN: 2375-2548 [Electronic] United States
• PMID: 38324683 (Publication Type: Journal Article)

Chemical References

• NLR Family, Pyrin Domain-Containing 3 Protein
• Intracellular Signaling Peptides and Proteins
• Inflammasomes
• Cysteine
• Gasdermins

Topics

• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Inflammasomes (metabolism)
• Cysteine (metabolism)
• Gasdermins
• Lipoylation