The Second Affiliated Hospital, Life Sciences Institute and School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; MOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
MOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Cell Rep. 2021 Aug 31;36(9):109541. doi: 10.1016/j.celrep.2021.109541.
The regulation of lipid homeostasis is not well understood. Using forward genetic screening, we demonstrate that the loss of dTBC1D22, an essential gene that encodes a Tre2-Bub2-Cdc16 (TBC) domain-containing protein, results in lipid droplet accumulation in multiple tissues. We observe that dTBC1D22 interacts with Rab40 and exhibits GTPase activating protein (GAP) activity. Overexpression of either the GTP- or GDP-binding-mimic form of Rab40 results in lipid droplet accumulation. We observe that Rab40 mutant flies are defective in lipid mobilization. The lipid depletion induced by overexpression of Brummer, a triglyceride lipase, is dependent on Rab40. Rab40 mutant flies exhibit decreased lipophagy and small size of autolysosomal structures, which may be due to the defective Golgi functions. Finally, we demonstrate that Rab40 physically interacts with Lamp1, and Rab40 is required for the distribution of Lamp1 during starvation. We propose that dTBC1D22 functions as a GAP for Rab40 to regulate lipophagy.
脂质动态平衡的调节机制尚未完全阐明。通过正向遗传学筛选，我们发现编码 Tre2-Bub2-Cdc16（TBC）结构域蛋白的必需基因 dTBC1D22 的缺失会导致多种组织中脂滴的积累。我们观察到 dTBC1D22 与 Rab40 相互作用，并表现出 GTP 酶激活蛋白（GAP）活性。Rab40 的 GTP 或 GDP 结合模拟物的过表达都会导致脂滴的积累。我们观察到 Rab40 突变的果蝇在脂滴动员方面存在缺陷。Brummer（一种甘油三酯脂肪酶）过表达诱导的脂质耗竭依赖于 Rab40。Rab40 突变的果蝇表现出自噬小体结构的噬脂作用减少和体积减小，这可能是由于高尔基体功能缺陷所致。最后，我们证明 Rab40 与 Lamp1 发生物理相互作用，并且 Rab40 在饥饿期间 Lamp1 的分布中是必需的。我们提出 dTBC1D22 作为 Rab40 的 GAP 发挥作用，以调节噬脂作用。
