IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-023-43650-z.html
   My bibliography  Save this article

Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice

Author

Listed:
  • Hai Ni

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Yinuo Wang

    (Chinese Academy of Sciences
    University of 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
    Shanghai Huashen Institute of Microbes and Infections)

  • Cliff Y. Yang

    (Sun Yat-sen University
    Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education)

  • Jijun Zhao

    (Sun Yat-sen University)

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.

Suggested Citation

  • Hai Ni & Yinuo Wang & Kai Yao & Ling Wang & Jiancheng Huang & Yongfang Xiao & Hongyao Chen & Bo Liu & Cliff Y. Yang & Jijun Zhao, 2024. "Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-43650-z
    DOI: 10.1038/s41467-023-43650-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43650-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-43650-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Shuyang Chen & Bo Zhu & Chengqian Yin & Wei Liu & Changpeng Han & Baoen Chen & Tongzheng Liu & Xin Li & Xiang Chen & Chunying Li & Limin Hu & Jun Zhou & Zhi-Xiang Xu & Xiumei Gao & Xu Wu & Colin R. Go, 2017. "Palmitoylation-dependent activation of MC1R prevents melanomagenesis," Nature, Nature, vol. 549(7672), pages 399-403, September.
    2. Mingming Zhang & Lixing Zhou & Yuejie Xu & Min Yang & Yilai Xu & Garrison Paul Komaniecki & Tatsiana Kosciuk & Xiao Chen & Xuan Lu & Xiaoping Zou & Maurine E. Linder & Hening Lin, 2020. "A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis," Nature, Nature, vol. 586(7829), pages 434-439, October.
    3. Sarah E. Ewald & Bettina L. Lee & Laura Lau & Katherine E. Wickliffe & Guo-Ping Shi & Harold A. Chapman & Gregory M. Barton, 2008. "The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor," Nature, Nature, vol. 456(7222), pages 658-662, December.
    4. Grant J. Brown & Pablo F. Cañete & Hao Wang & Arti Medhavy & Josiah Bones & Jonathan A. Roco & Yuke He & Yuting Qin & Jean Cappello & Julia I. Ellyard & Katharine Bassett & Qian Shen & Gaetan Burgio &, 2022. "TLR7 gain-of-function genetic variation causes human lupus," Nature, Nature, vol. 605(7909), pages 349-356, May.
    5. You-Me Kim & Melanie M. Brinkmann & Marie-Eve Paquet & Hidde L. Ploegh, 2008. "UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes," Nature, Nature, vol. 452(7184), pages 234-238, March.
    6. Roberto Lande & Josh Gregorio & Valeria Facchinetti & Bithi Chatterjee & Yi-Hong Wang & Bernhard Homey & Wei Cao & Yui-Hsi Wang & Bing Su & Frank O. Nestle & Tomasz Zal & Ira Mellman & Jens-Michael Sc, 2007. "Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide," Nature, Nature, vol. 449(7162), pages 564-569, October.
    7. Olivia Majer & Bo Liu & Brian J. Woo & Lieselotte S. M. Kreuk & Erik Dis & Gregory M. Barton, 2019. "Release from UNC93B1 reinforces the compartmentalized activation of select TLRs," Nature, Nature, vol. 575(7782), pages 371-374, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Feiyang Ma & Olesya Plazyo & Allison C. Billi & Lam C. Tsoi & Xianying Xing & Rachael Wasikowski & Mehrnaz Gharaee-Kermani & Grace Hile & Yanyun Jiang & Paul W. Harms & Enze Xing & Joseph Kirma & Jing, 2023. "Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Yoann Saucereau & Thomas H. Wilson & Matthew C. K. Tang & Martin C. Moncrieffe & Steven W. Hardwick & Dimitri Y. Chirgadze & Sandro G. Soares & Maria Jose Marcaida & Nicholas J. Gay & Monique Gangloff, 2022. "Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Andras Boeszoermenyi & Léa Bernaleau & Xudong Chen & Felix Kartnig & Min Xie & Haobo Zhang & Sensen Zhang & Maeva Delacrétaz & Anna Koren & Ann-Katrin Hopp & Vojtech Dvorak & Stefan Kubicek & Daniel A, 2023. "A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Xudong Chen & Min Xie & Sensen Zhang & Marta Monguió-Tortajada & Jian Yin & Chang Liu & Youqi Zhang & Maeva Delacrétaz & Mingyue Song & Yixue Wang & Lin Dong & Qiang Ding & Boda Zhou & Xiaolin Tian & , 2023. "Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Do-Won Jeong & Jong-Wan Park & Kyeong Seog Kim & Jiyoung Kim & June Huh & Jieun Seo & Ye Lee Kim & Joo-Youn Cho & Kwang-Woong Lee & Junji Fukuda & Yang-Sook Chun, 2023. "Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Weirong Chen & So-Hee Hong & Scott A. Jenks & Fabliha A. Anam & Christopher M. Tipton & Matthew C. Woodruff & Jennifer R. Hom & Kevin S. Cashman & Caterina Elisa Faliti & Xiaoqian Wang & Shuya Kyu & C, 2024. "Distinct transcriptomes and autocrine cytokines underpin maturation and survival of antibody-secreting cells in systemic lupus erythematosus," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Antonio Julià & Alba Erra & Carles Palacio & Carlos Tomas & Xavier Sans & Pere Barceló & Sara Marsal, 2009. "An Eight-Gene Blood Expression Profile Predicts the Response to Infliximab in Rheumatoid Arthritis," PLOS ONE, Public Library of Science, vol. 4(10), pages 1-8, October.
    8. Wen-Lan Yang & Weinan Qiu & Ting Zhang & Kai Xu & Zi-Juan Gu & Yu Zhou & Heng-Ji Xu & Zhong-Zhou Yang & Bin Shen & Yong-Liang Zhao & Qi Zhou & Ying Yang & Wei Li & Peng-Yuan Yang & Yun-Gui Yang, 2023. "Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Chao Yang & Mahesh Bachu & Yong Du & Caroline Brauner & Ruoxi Yuan & Marie Dominique Ah Kioon & Giancarlo Chesi & Franck J. Barrat & Lionel B. Ivashkiv, 2022. "CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    10. Eileen Rauch & Timm Amendt & Aleksandra Lopez Krol & Fabian B. Lang & Vincent Linse & Michelle Hohmann & Ann-Christin Keim & Susanne Kreutzer & Kevin Kawengian & Malte Buchholz & Philipp Duschner & Sa, 2024. "T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    11. Lu Jia & Yiyang Jiang & Lili Wu & Jingfei Fu & Juan Du & Zhenhua Luo & Lijia Guo & Junji Xu & Yi Liu, 2024. "Porphyromonas gingivalis aggravates colitis via a gut microbiota-linoleic acid metabolism-Th17/Treg cell balance axis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    12. Silke M Currie & Emily Gwyer Findlay & Brian J McHugh & Annie Mackellar & Tian Man & Derek Macmillan & Hongwei Wang & Paul M Fitch & Jürgen Schwarze & Donald J Davidson, 2013. "The Human Cathelicidin LL-37 Has Antiviral Activity against Respiratory Syncytial Virus," PLOS ONE, Public Library of Science, vol. 8(8), pages 1-10, August.
    13. Yasunori Shintani & Hannes CA Drexler & Hidetaka Kioka & Cesare MN Terracciano & Steven R Coppen & Hiromi Imamura & Masaharu Akao & Junichi Nakai & Ann P Wheeler & Shuichiro Higo & Hiroyuki Nakayama &, 2014. "Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2," Nature, Nature, vol. 15(4), pages 438-445, April.
    14. Srujan Kumar Dondapati & Georg Pietruschka & Lena Thoring & Doreen A Wüstenhagen & Stefan Kubick, 2019. "Cell-free synthesis of human toll-like receptor 9 (TLR9): Optimization of synthesis conditions and functional analysis," PLOS ONE, Public Library of Science, vol. 14(4), pages 1-16, April.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-43650-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.