title: Lysosomal calcium signalling regulates autophagy through calcineurin and ​TFEB.
abstract: 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.
authors.forename: Diego L
authors.initials: DL
authors.lastname: Medina
authors.forename: Simone
authors.initials: S
authors.lastname: Di Paola
authors.forename: Ivana
authors.initials: I
authors.lastname: Peluso
authors.forename: Andrea
authors.initials: A
authors.lastname: Armani
authors.forename: Diego
authors.initials: D
authors.lastname: De Stefani
authors.forename: Rossella
authors.initials: R
authors.lastname: Venditti
authors.forename: Sandro
authors.initials: S
authors.lastname: Montefusco
authors.forename: Anna
authors.initials: A
authors.lastname: Scotto-Rosato
authors.forename: Carolina
authors.initials: C
authors.lastname: Prezioso
authors.forename: Alison
authors.initials: A
authors.lastname: Forrester
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.forename: Wuyang
authors.initials: W
authors.lastname: Wang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.forename: Haoxing
authors.initials: H
authors.lastname: Xu
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Matteis
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D021381:Protein Transport; D050051:Transient Receptor Potential Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C416674:MCOLN1 protein, human; C064972:TFEB protein, human; D050051:Transient Receptor Potential Channels; D019703:Calcineurin