2. Academic Validation
  3. Regulation of lipid homeostasis by the TBC protein dTBC1D22 via modulation of the small GTPase Rab40 to facilitate lipophagy

Regulation of lipid homeostasis by the TBC protein dTBC1D22 via modulation of the small GTPase Rab40 to facilitate lipophagy

  • Cell Rep. 2021 Aug 31;36(9):109541. doi: 10.1016/j.celrep.2021.109541.
Xiuying Duan 1,  Lingna Xu 1,  Yawen Li 2,  Lijun Jia 2,  Wei Liu 1,  Wenxia Shao 2,  Vafa Bayat 3,  Weina Shang 2,  Liquan Wang 4,  Jun-Ping Liu 5,  Chao Tong 6
Affiliations

Affiliations

  • 1 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.
  • 2 MOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 3 Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 The Second Affiliated Hospital, Life Sciences Institute and School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 5 Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 6 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; Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: ctong@zju.edu.cn.
PMID: 34469730 DOI: 10.1016/j.celrep.2021.109541
Abstract

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.

Keywords

Drosophila; GTPase-activating proteins (GAPs); Golgi; Rab GTPase; Rab40; TBC domain-containing protein; autophagy; lipophagy; lysosome.

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