Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation.
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.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and.
Wuyang
W
Wang
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and.
Qiong
Q
Gao
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and.
Meimei
M
Yang
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and.
Xiaoli
X
Zhang
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and.
Lu
L
Yu
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and.
Maria
M
Lawas
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and.
Xinran
X
Li
National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850.
Marthe
M
Bryant-Genevier
National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850.
Noel T
NT
Southall
National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850.
Juan
J
Marugan
National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850.
Marc
M
Ferrer
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and haoxingx@umich.edu.
Haoxing
H
Xu
D000596:Amino Acids / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009542:Niemann-Pick Diseases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D014176:Protein Biosynthesis; D021381:Protein Transport; D059748:Proteolysis; D012964:Sodium / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D015854:Up-Regulation
D000596:Amino Acids; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C416674:MCOLN1 protein, human; D018129:Phosphatidylinositol Phosphates; D050051:Transient Receptor Potential Channels; C106336:phosphatidylinositol 3,5-diphosphate; D002784:Cholesterol; D012964:Sodium; D058570:TOR Serine-Threonine Kinases; D002118:Calcium
TFEB; TRPML1; lysosome; mTOR; starvation