Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice

Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice

02 January 2024 | Hai Ni, Yinuo Wang, Kai Yao, Ling Wang, Jiancheng Huang, Yongfang Xiao, Hongyao Chen, Bo Liu, Cliff Y. Yang, Jijun Zhao
This study investigates the role of palmitoyl-protein thioesterase 1 (PPT1) in regulating Toll-like receptor 9 (TLR9) signaling and systemic autoimmunity in mice. TLR9 plays a crucial role in recognizing self-DNA and is implicated in the pathogenesis of systemic lupus erythematosus (SLE). The study reveals that PPT1 regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of type I interferon (IFNα) by plasmacytoid dendritic cells (pDCs) and tumor necrosis factor (TNF) by macrophages. Genetic deficiency or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice, a model of SLE. In healthy volunteers and patients with SLE, the PPT1 inhibitor HDSF reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrate that TLR9 is S-palmitoylated at C258 and C265. The protein acyltransferase DHHC3 palmitoylates TLR9 in the Golgi and regulates its trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. The study reveals a posttranslational modification cycle that controls TLR9 response and autoimmunity, suggesting PPT1 as a potential immunotherapeutic target for treating autoimmune diseases.This study investigates the role of palmitoyl-protein thioesterase 1 (PPT1) in regulating Toll-like receptor 9 (TLR9) signaling and systemic autoimmunity in mice. TLR9 plays a crucial role in recognizing self-DNA and is implicated in the pathogenesis of systemic lupus erythematosus (SLE). The study reveals that PPT1 regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of type I interferon (IFNα) by plasmacytoid dendritic cells (pDCs) and tumor necrosis factor (TNF) by macrophages. Genetic deficiency or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice, a model of SLE. In healthy volunteers and patients with SLE, the PPT1 inhibitor HDSF reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrate that TLR9 is S-palmitoylated at C258 and C265. The protein acyltransferase DHHC3 palmitoylates TLR9 in the Golgi and regulates its trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. The study reveals a posttranslational modification cycle that controls TLR9 response and autoimmunity, suggesting PPT1 as a potential immunotherapeutic target for treating autoimmune diseases.
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