ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation

Sihao Zheng; Xiangyong Que; Shuxian Wang; Qi Zhou; Xiaoke Xing; Liang Chen; Chunyan Hou; Junfeng Ma; Ping An; Yihan Peng; Yi Yao; Qibin Song; Juanjuan Li; Pingfeng Zhang; Huadong Pei

doi:10.1016/j.molcel.2023.11.015

ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation

Mol Cell. 2023 Dec 21;83(24):4570-4585.e7. doi: 10.1016/j.molcel.2023.11.015. Epub 2023 Dec 12.

Authors

Sihao Zheng¹, Xiangyong Que², Shuxian Wang¹, Qi Zhou², Xiaoke Xing¹, Liang Chen¹, Chunyan Hou³, Junfeng Ma³, Ping An⁴, Yihan Peng³, Yi Yao¹, Qibin Song⁵, Juanjuan Li⁶, Pingfeng Zhang⁷, Huadong Pei⁸

Affiliations

¹ Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
² Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China; Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
³ Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
⁴ Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan, China.
⁵ Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address: qibinsong@whu.edu.cn.
⁶ Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address: juanjuan.li@whu.edu.cn.
⁷ Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address: pingfeng.zhang@whu.edu.cn.
⁸ Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address: huadong.pei@georgetown.edu.

PMID: 38092000
DOI: 10.1016/j.molcel.2023.11.015

Abstract

The nucleotide-binding domain (NBD), leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a critical mediator of the innate immune response. How NLRP3 responds to stimuli and initiates the assembly of the NLRP3 inflammasome is not fully understood. Here, we found that a cellular metabolite, palmitate, facilitates NLRP3 activation by enhancing its S-palmitoylation, in synergy with lipopolysaccharide stimulation. NLRP3 is post-translationally palmitoylated by zinc-finger and aspartate-histidine-histidine-cysteine 5 (ZDHHC5) at the LRR domain, which promotes NLRP3 inflammasome assembly and activation. Silencing ZDHHC5 blocks NLRP3 oligomerization, NLRP3-NEK7 interaction, and formation of large intracellular ASC aggregates, leading to abrogation of caspase-1 activation, IL-1β/18 release, and GSDMD cleavage, both in human cells and in mice. ABHD17A depalmitoylates NLRP3, and one human-heritable disease-associated mutation in NLRP3 was found to be associated with defective ABHD17A binding and hyper-palmitoylation. Furthermore, Zdhhc5^-/- mice showed defective NLRP3 inflammasome activation in vivo. Taken together, our data reveal an endogenous mechanism of inflammasome assembly and activation and suggest NLRP3 palmitoylation as a potential target for the treatment of NLRP3 inflammasome-driven diseases.

Keywords: ABHD17A; NEK7; NLRP3; ZDHHC5 palmitoyltransferase; inflammasome activation; palmitoylation.

MeSH terms

Acyltransferases* / genetics
Acyltransferases* / metabolism
Animals
Caspase 1 / metabolism
Histidine / metabolism
Humans
Inflammasomes* / metabolism
Interleukin-1beta / metabolism
Lipoylation
Macrophages / metabolism
Mice
NIMA-Related Kinases / genetics
NIMA-Related Kinases / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism

Substances

Caspase 1
Histidine
Inflammasomes
Interleukin-1beta
NEK7 protein, human
NIMA-Related Kinases
NLR Family, Pyrin Domain-Containing 3 Protein
ZDHHC5 protein, human
Acyltransferases