Lipid droplets (LDs) are critical for lipid storage and energy metabolism. LDs form in the endoplasmic reticulum (ER). However, the molecular basis for LD biogenesis remains elusive. Here, we show that fat storage–inducing transmembrane protein 2 (FIT2) interacts with ER tubule-forming proteins Rtn4 and REEP5. The association is mainly transmembrane domain based and stimulated by oleic acid. Depletion of ER tubule-forming proteins decreases the number and size of LDs in cells and Caenorhabditis elegans, mimicking loss of FIT2. Through cytosolic loops, FIT2 binds to cytoskeletal protein septin 7, an interaction that is also required for normal LD biogenesis. Depletion of ER tubule-forming proteins or septins delays nascent LD formation. In addition, FIT2-interacting proteins are up-regulated during adipocyte differentiation, and ER tubule-forming proteins, septin 7, and FIT2 are transiently enriched at LD formation sites. Thus, FIT2-mediated nascent LD biogenesis is facilitated by ER tubule-forming proteins and septins.
FIT2 organizes lipid droplet biogenesis with ER tubule-forming proteins and septins
F. Chen’s present address is Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Fang Chen, Bing Yan, Jie Ren, Rui Lyu, Yanfang Wu, Yuting Guo, Dong Li, Hong Zhang, Junjie Hu; FIT2 organizes lipid droplet biogenesis with ER tubule-forming proteins and septins. J Cell Biol 3 May 2021; 220 (5): e201907183. doi: https://doi.org/10.1083/jcb.201907183
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