Qa-SNARE syntaxin 18 mediates lipid droplet fusion with SNAP23 and SEC22B

Yuhui Fu; Binbin Ding; Xiaoxia Liu; Shangang Zhao; Fang Chen; Linsen Li; Yi Zhu; Jingxuan Zhao; Zhen Yuan; Yafeng Shen; Chaofeng Yang; Mengle Shao; She Chen; Perry E Bickel; Qing Zhong

doi:10.1038/s41421-023-00613-4

Qa-SNARE syntaxin 18 mediates lipid droplet fusion with SNAP23 and SEC22B

Cell Discov. 2023 Nov 21;9(1):115. doi: 10.1038/s41421-023-00613-4.

Authors

Yuhui Fu^#¹, Binbin Ding^#², Xiaoxia Liu^#³, Shangang Zhao⁴, Fang Chen¹, Linsen Li¹, Yi Zhu⁵, Jingxuan Zhao⁶, Zhen Yuan⁷, Yafeng Shen⁸, Chaofeng Yang⁹, Mengle Shao¹⁰, She Chen¹¹, Perry E Bickel⁹, Qing Zhong¹²

Affiliations

¹ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. dingbinbin1988@163.com.
³ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. xxliu@shsmu.edu.cn.
⁴ Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology and Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁵ Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁶ MedChem Service Unit of Shanghai Haoyuan Chemexpress Co., Ltd., Shanghai, China.
⁷ Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁸ Shanghai Institute of Precision of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁹ Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁰ CAS Key Laboratory of Molecular Virology and Immunology, The Center for Microbes, Development and Health, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
¹¹ National Institute of Biological Sciences, Beijing, China.
¹² Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. qingzhong@shsmu.edu.cn.

^# Contributed equally.

Abstract

Lipid droplets (LDs) are dynamic lipid storage organelles that can sense and respond to changes in systemic energy balance. The size and number of LDs are controlled by complex and delicate mechanisms, among which, whether and which SNARE proteins mediate LD fusion, and the mechanisms governing this process remain poorly understood. Here we identified a SNARE complex, syntaxin 18 (STX18)-SNAP23-SEC22B, that is recruited to LDs to mediate LD fusion. STX18 targets LDs with its transmembrane domain spanning the phospholipid monolayer twice. STX18-SNAP23-SEC22B complex drives LD fusion in adiposome lipid mixing and content mixing in vitro assays. CIDEC/FSP27 directly binds STX18, SEC22B, and SNAP23, and promotes the lipid mixing of SNAREs-reconstituted adiposomes by promoting LD clustering. Knockdown of STX18 in mouse liver via AAV resulted in smaller liver and reduced LD size under high-fat diet conditions. All these results demonstrate a critical role of the SNARE complex STX18-SNAP23-SEC22B in LD fusion.

Grants and funding

R01 DK115875/DK/NIDDK NIH HHS/United States