@article{44c8c6f862e547fd8fa809188b1c6010,
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 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.",
author = "Medina, {Diego L.} and {Di Paola}, Simone and Ivana Peluso and Andrea Armani and {De Stefani}, Diego and Rossella Venditti and Sandro Montefusco and Anna Scotto-Rosato and Carolina Prezioso and Alison Forrester and Carmine Settembre and Wuyang Wang and Qiong Gao and Haoxing Xu and Marco Sandri and Rosario Rizzuto and {De Matteis}, {Maria Antonietta} and Andrea Ballabio",
note = "Funding Information: We thank J. Meldolesi, T. Pozzan, D. Rubinsztein and R. Polishchuk for helpful suggestions and critical review of the manuscript. We thank G. Diez-Roux and A. Burton for their support in manuscript preparation. We are also grateful to R. De Cegli and D. Carrella for their support in the statistical analysis of the results. The TIGEM Bioinformatic and High Content Screening Facilities are gratefully acknowledged for their technological contributions to the project. We also thank J. D. Molkentin for the CanB KO MEFs, B. A. Rothermel for the HA–ΔCnA, and P. Aza-Blanc for suggestions on the reverse transfection protocol. We acknowledge the support of the Italian Telethon Foundation grant numbers TGM11CB6 (A.B.); the Beyond Batten Disease Foundation (A.B.); European Research Council Advanced Investigator grant no. 250154 (CLEAR) (A.B.); US National Institutes of Health (R01-NS078072) (A.B.); Telethon-Italy (TCP04009) (M.S.), European Research Council Consolidator grant no. 282310-(MyoPHAGY) (M.S.). Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",
year = "2015",
month = mar,
day = "2",
doi = "10.1038/ncb3114",
language = "English",
volume = "17",
pages = "288--299",
journal = "nature cell biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "3",
}