Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation.

Therapeutic Approaches

Abstract

Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca(2+) channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca(2+) imaging and whole-lysosome patch clamping, lysosomal Ca(2+) release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na(+)-selective currents were not up-regulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca(2+) signaling.

Authors

Wang, Wuyang; Gao, Qiong; Yang, Meimei; Zhang, Xiaoli; Yu, Lu; Lawas, Maria; Li, Xinran; Bryant-Genevier, Marthe; Southall, Noel; Marugan, Juan; Ferrer-Alegre, Marc; Xu, Haoxing;

Keywords

  • Amino Acids/ deficiency
  • Amino Acids/ metabolism
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/ metabolism
  • Calcium/ metabolism
  • Cell Line
  • Cell Nucleus/ metabolism
  • Cholesterol/ metabolism
  • Gene Expression Regulation
  • Humans
  • Lysosomes/ metabolism
  • Mutation/ genetics
  • Niemann-Pick Diseases/ metabolism
  • Phosphatidylinositol Phosphates/ metabolism
  • Protein Biosynthesis
  • Protein Transport
  • Proteolysis
  • Sodium/ metabolism
  • TOR Serine-Threonine Kinases/ metabolism
  • Transcription, Genetic
  • Transient Receptor Potential Channels/ metabolism
  • Up-Regulation

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