Lysosomal calcium signalling regulates autophagy through calcineurin and ​TFEB

Nat Cell Biol. 2015 Mar;17(3):288-99. doi: 10.1038/ncb3114.


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 Ca2+ signalling mechanism controls the activities of the phosphatase calcineurin and of its substrate ​TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca2+ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Calcineurin / genetics*
  • Calcineurin / metabolism
  • Calcium Signaling
  • Cell Line, Tumor
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Humans
  • Lysosomes / metabolism*
  • Mice
  • Phosphorylation
  • Protein Transport
  • Transient Receptor Potential Channels / genetics*
  • Transient Receptor Potential Channels / metabolism


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • MCOLN1 protein, human
  • TFEB protein, human
  • Transient Receptor Potential Channels
  • Calcineurin