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Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB
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Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB
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Journal Article
Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB
2015
Overview
The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca
2+
signalling mechanism controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca
2+
release through mucolipin 1 (MCOLN1) activates calcineurin, which binds and dephosphorylates TFEB, thus promoting its nuclear translocation. Genetic and pharmacological inhibition of calcineurin suppressed TFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect. Induction of autophagy and lysosomal biogenesis through TFEB required MCOLN1-mediated calcineurin activation. These data link lysosomal calcium signalling to both calcineurin regulation and autophagy induction and identify the lysosome as a hub for the signalling pathways that regulate cellular homeostasis.
Medina, Ballabio and colleagues report that calcium release from the lysosome stimulates calcineurin, which dephosphorylates and activates TFEB. These findings reveal a central role for calcium signalling in autophagy and lysosome homeostasis.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 14
/ 38
/ 42
/ 45
/ 49
/ 64/60
/ 82
/ 96
/ Animals
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
/ Calcium
/ Cellular signal transduction
/ Humans
/ Mice
/ Transient Receptor Potential Channels - genetics
