Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice
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 systemi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43650-z |
| _version_ | 1797363156051296256 |
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| author | Hai Ni Yinuo Wang Kai Yao Ling Wang Jiancheng Huang Yongfang Xiao Hongyao Chen Bo Liu Cliff Y. Yang Jijun Zhao |
| author_facet | Hai Ni Yinuo Wang Kai Yao Ling Wang Jiancheng Huang Yongfang Xiao Hongyao Chen Bo Liu Cliff Y. Yang Jijun Zhao |
| author_sort | Hai Ni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:16:38Z |
| format | Article |
| id | doaj.art-b6fac866b0354c3396890900d9bbc14f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:38Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b6fac866b0354c3396890900d9bbc14f2024-01-07T12:33:45ZengNature PortfolioNature Communications2041-17232024-01-0115111710.1038/s41467-023-43650-zCyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in miceHai Ni0Yinuo Wang1Kai Yao2Ling Wang3Jiancheng Huang4Yongfang Xiao5Hongyao Chen6Bo Liu7Cliff Y. Yang8Jijun Zhao9Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen UniversityCAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of SciencesDepartment of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen UniversityCAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of SciencesDepartment of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen UniversityAbstract 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.https://doi.org/10.1038/s41467-023-43650-z |
| spellingShingle | Hai Ni Yinuo Wang Kai Yao Ling Wang Jiancheng Huang Yongfang Xiao Hongyao Chen Bo Liu Cliff Y. Yang Jijun Zhao Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice Nature Communications |
| title | Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice |
| title_full | Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice |
| title_fullStr | Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice |
| title_full_unstemmed | Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice |
| title_short | Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice |
| title_sort | cyclical palmitoylation regulates tlr9 signalling and systemic autoimmunity in mice |
| url | https://doi.org/10.1038/s41467-023-43650-z |
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