Acetylation is required for full activation of the NLRP3 inflammasome

Yening Zhang, Ling Luo, Xueming Xu, Jianfeng Wu, Fupeng Wang, Yanyan Lu, Ningjie Zhang, Yingying Ding, Ben Lu () and Kai Zhao ()
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Yening Zhang: the Third Xiangya Hospital, Central South University
Ling Luo: the Third Xiangya Hospital, Central South University
Xueming Xu: the Third Xiangya Hospital, Central South University
Jianfeng Wu: School of Life Sciences, Xiamen University
Fupeng Wang: the Third Xiangya Hospital, Central South University
Yanyan Lu: The Second Xiangya Hospital, Central South University
Ningjie Zhang: The Second Xiangya Hospital, Central South University
Yingying Ding: NavaMedical University
Ben Lu: the Third Xiangya Hospital, Central South University
Kai Zhao: the Third Xiangya Hospital, Central South University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Full activation of the NLRP3 inflammasome needs two sequential signals: a priming signal, followed by a second, assembly signal. Several studies have shown that the two signals trigger post-translational modification (PTM) of NLRP3, affecting activity of the inflammasome, however, the PTMs induced by the second signal are less well characterized. Here, we show that the assembly signal involves acetylation of NLRP3 at lysine 24, which is important for the oligomerization and the actual assembly of NLRP3 without affecting its recruitment to dispersed trans-Golgi network (dTGN). Accordingly, NLRP3 inflammasome activation is impaired in NLRP3-K24R knock-in mice. We identify KAT5 as an acetyltransferase able to acetylate NLRP3. KAT5 deficiency in myeloid cells and pharmacological inhibition of KAT5 enzymatic activity reduce activation of the NLRP3 inflammasome, both in vitro and in vivo. Thus, our study reveals a key mechanism for the oligomerization and full activation of NLRP3 and lays down the proof of principle for therapeutic targeting of the KAT5-NLRP3 axis.

Date: 2023
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DOI: 10.1038/s41467-023-44203-0

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