Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB

Diego L. Medina; Simone Di Paola; Ivana Peluso; Andrea Armani; Diego De Stefani; Rossella Venditti; Sandro Montefusco; Anna Scotto-Rosato; Carolina Prezioso; Alison Forrester; Carmine Settembre; Wuyang Wang; Qiong Gao; Haoxing Xu; Marco Sandri; Rosario Rizzuto; Maria Antonietta De Matteis; Andrea Ballabio

doi:10.1038/ncb3114

Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB

Diego L. Medina, Simone Di Paola, Ivana Peluso, Andrea Armani, Diego De Stefani, Rossella Venditti, Sandro Montefusco, Anna Scotto-Rosato, Carolina Prezioso, Alison Forrester, Carmine Settembre, Wuyang Wang, Qiong Gao, Haoxing Xu, Marco Sandri, Rosario Rizzuto, Maria Antonietta De Matteis, Andrea Ballabio

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	288-299
Number of pages	12
Journal	nature cell biology
Volume	17
Issue number	3
DOIs	https://doi.org/10.1038/ncb3114
Publication status	Published - 2 Mar 2015
Externally published	Yes

Funding

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.).

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Medina, D. L., Di Paola, S., Peluso, I., Armani, A., De Stefani, D., Venditti, R., Montefusco, S., Scotto-Rosato, A., Prezioso, C., Forrester, A., Settembre, C., Wang, W., Gao, Q., Xu, H., Sandri, M., Rizzuto, R., De Matteis, M. A., & Ballabio, A. (2015). Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. nature cell biology, 17(3), 288-299. https://doi.org/10.1038/ncb3114

@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",

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journal = "nature cell biology",

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Medina, DL, Di Paola, S, Peluso, I, Armani, A, De Stefani, D, Venditti, R, Montefusco, S, Scotto-Rosato, A, Prezioso, C, Forrester, A, Settembre, C, Wang, W, Gao, Q, Xu, H, Sandri, M, Rizzuto, R, De Matteis, MA & Ballabio, A 2015, 'Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB', nature cell biology, vol. 17, no. 3, pp. 288-299. https://doi.org/10.1038/ncb3114

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T1 - Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB

AU - Medina, Diego L.

AU - Di Paola, Simone

AU - Peluso, Ivana

AU - Armani, Andrea

AU - De Stefani, Diego

AU - Venditti, Rossella

AU - Montefusco, Sandro

AU - Scotto-Rosato, Anna

AU - Prezioso, Carolina

AU - Forrester, Alison

AU - Settembre, Carmine

AU - Wang, Wuyang

AU - Gao, Qiong

AU - Xu, Haoxing

AU - Sandri, Marco

AU - Rizzuto, Rosario

AU - De Matteis, Maria Antonietta

AU - Ballabio, Andrea

N1 - 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: © 2015 Macmillan Publishers Limited.

PY - 2015/3/2

Y1 - 2015/3/2

N2 - 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.

AB - 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.

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DO - 10.1038/ncb3114

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VL - 17

SP - 288

EP - 299

JO - nature cell biology

JF - nature cell biology

IS - 3

ER -

Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB

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