Fu Yuhui, Ding Binbin, Liu Xiaoxia, Zhao Shangang, Chen Fang, Li Linsen, Zhu Yi, Zhao Jingxuan, Yuan Zhen, Shen Yafeng, Yang Chaofeng, Shao Mengle, Chen She, Bickel Perry E, Zhong Qing
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Cell Discov. 2023 Nov 21;9(1):115. doi: 10.1038/s41421-023-00613-4.
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.
脂滴（LDs）是动态的脂质储存细胞器，能够感知并响应全身能量平衡的变化。脂滴的大小和数量受复杂而精细的机制控制，其中，是否以及哪些SNARE蛋白介导脂滴融合，以及调控这一过程的机制仍知之甚少。在此，我们鉴定出一种SNARE复合体，即 syntaxin 18（STX18）-SNAP23-SEC22B，它被招募至脂滴以介导脂滴融合。STX18通过其跨膜结构域两次跨越磷脂单层靶向脂滴。在体外测定中，STX18-SNAP23-SEC22B复合体在脂质体脂质混合和内容物混合过程中驱动脂滴融合。CIDEC/FSP27直接结合STX18、SEC22B和SNAP23，并通过促进脂滴聚集来促进SNAREs重组脂质体的脂质混合。通过腺相关病毒（AAV）敲低小鼠肝脏中的STX18，在高脂饮食条件下导致肝脏变小且脂滴尺寸减小。所有这些结果都证明了SNARE复合体STX18-SNAP23-SEC22B在脂滴融合中起关键作用。
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