The Cyclopeptide Astin C Specifically Inhibits the Innate Immune CDN Sensor STING

Senlin Li; Ze Hong; Zhe Wang; Fei Li; Jiahao Mei; Lulu Huang; Xiwen Lou; Simeng Zhao; Lihua Song; Wei Chen; Qiang Wang; Heng Liu; Yanni Cai; Huansha Yu; Huimin Xu; Guangzhi Zeng; Quanyi Wang; Juanjuan Zhu; Xing Liu; Ninghua Tan; Chen Wang

doi:10.1016/j.celrep.2018.11.097

The Cyclopeptide Astin C Specifically Inhibits the Innate Immune CDN Sensor STING

Cell Rep. 2018 Dec 18;25(12):3405-3421.e7. doi: 10.1016/j.celrep.2018.11.097.

Authors

Senlin Li¹, Ze Hong², Zhe Wang³, Fei Li⁴, Jiahao Mei², Lulu Huang⁵, Xiwen Lou⁶, Simeng Zhao⁴, Lihua Song², Wei Chen⁵, Qiang Wang⁵, Heng Liu⁵, Yanni Cai⁵, Huansha Yu⁵, Huimin Xu⁴, Guangzhi Zeng⁴, Quanyi Wang², Juanjuan Zhu², Xing Liu⁷, Ninghua Tan⁸, Chen Wang⁹

Affiliations

¹ State Key Laboratory of Natural Medicines, School of Life Science and Technology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, China; State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
² State Key Laboratory of Natural Medicines, School of Life Science and Technology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, China.
³ State Key Laboratory of Natural Medicines, School of Life Science and Technology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
⁴ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
⁵ State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
⁶ Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
⁷ Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China. Electronic address: xingliu@ips.ac.cn.
⁸ State Key Laboratory of Natural Medicines, School of Life Science and Technology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: nhtan@cpu.edu.cn.
⁹ State Key Laboratory of Natural Medicines, School of Life Science and Technology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, China; State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. Electronic address: cwang1971@cpu.edu.cn.

PMID: 30566866
DOI: 10.1016/j.celrep.2018.11.097

Abstract

cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1^-/- BMDM cells and in Trex1^-/- mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.

Keywords: HSV-1; IRF3; STING; TBK1; astin C; autoimmune diseases; cGAS; cyclopeptide; innate immunity; therapeutic target.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Infective Agents / metabolism
Autoimmune Diseases / drug therapy
Cytosol / metabolism
DNA / metabolism
Female
Gene Expression Regulation / drug effects
HEK293 Cells
Herpesvirus 1, Human / drug effects
Humans
Immunity, Innate / drug effects*
Inflammation / pathology
Interferon Regulatory Factor-3 / metabolism
Listeria monocytogenes / drug effects
Male
Membrane Proteins / chemistry
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Nucleotides / metabolism*
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Peptides, Cyclic / therapeutic use
RAW 264.7 Cells
Signal Transduction

Substances

Anti-Infective Agents
Interferon Regulatory Factor-3
Membrane Proteins
Nucleotides
Peptides, Cyclic
Sting1 protein, mouse
astin C
DNA