Referenced in: none

Automatically associated channels: TRP , TRPM , TRPML , TRPML1

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

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

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2015 Mar 17 , 112, E1373-81

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25733853

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.