Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice

Hai Ni, Yinuo Wang, Kai Yao, Ling Wang, Jiancheng Huang, Yongfang Xiao, Hongyao Chen, Bo Liu (), Cliff Y. Yang () and Jijun Zhao ()
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Hai Ni: Sun Yat-sen University
Yinuo Wang: Chinese Academy of Sciences
Kai Yao: Sun Yat-sen University
Ling Wang: Sun Yat-sen University
Jiancheng Huang: Sun Yat-sen University
Yongfang Xiao: Sun Yat-sen University
Hongyao Chen: Sun Yat-sen University
Bo Liu: Chinese Academy of Sciences
Cliff Y. Yang: Sun Yat-sen University
Jijun Zhao: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl-protein thioesterase 1 (PPT1) regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TNF by macrophages. Genetic deficiency in or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with SLE, the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltransferase, DHHC3, palmitoylates TLR9 in the Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. Our results reveal a posttranslational modification cycle that controls TLR9 response and autoimmunity.

Date: 2024
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DOI: 10.1038/s41467-023-43650-z

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