The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1

J. M. Vicencio; C. Ortiz; A. Criollo; A. W.E. Jones; O. Kepp; L. Galluzzi; N. Joza; I. Vitale; E. Morselli; M. Tailler; M. Castedo; M. C. Maiuri; J. Molgó; G. Szabadkai; S. Lavandero; G. Kroemer

doi:10.1038/cdd.2009.34

The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1

J. M. Vicencio, C. Ortiz, A. Criollo, A. W.E. Jones, O. Kepp, L. Galluzzi, N. Joza, I. Vitale, E. Morselli, M. Tailler, M. Castedo, M. C. Maiuri, J. Molgó, G. Szabadkai, S. Lavandero, G. Kroemer

Universidad de Chile

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

256 Citations (Scopus)

Abstract

The inositol 1,4,5-trisphosphate receptor (IP₃R) is a major regulator of apoptotic signaling. Through interactions with members of the Bcl-2 family of proteins, it drives calcium (Ca²⁺) transients from the endoplasmic reticulum (ER) to mitochondria, thereby establishing a functional and physical link between these organelles. Importantly, the IP₃R also regulates autophagy, and in particular, its inhibition/depletion strongly induces macroautophagy. Here, we show that the IP₃R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed by the IP₃ R and Beclin 1, an interaction that is increased or inhibited by overexpression or knockdown of Bcl-2, respectively. An effect of Beclin 1 on Ca²⁺ homeostasis was discarded as siRNA-mediated knockdown of Beclin 1 did not affect cytosolic or luminal ER Ca²⁺ levels. Xestospongin B- or starvation-induced autophagy was inhibited by overexpression of the IP₃R ligand-binding domain, which coimmunoprecipitated with Beclin 1. These results identify IP₃R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.

Original language	English
Pages (from-to)	1006-1017
Number of pages	12
Journal	Cell Death and Differentiation
Volume	16
Issue number	7
DOIs	https://doi.org/10.1038/cdd.2009.34
Publication status	Published - 2009

Bibliographical note

Funding Information:
Acknowledgements. GK is supported by the Ligue Nationale contre le Cancer (équipe labellisée), European Commission (RIGHT, ChemoRes, Apop-Train, Apo-SYs), Agence Nationale pour la Recherche, Cancéropôle Ile-de-France and Institut National contre le Cancer (INCa). We thank the International Collaboration Program ECOS-CONICYT, project C08S01. JMV is supported by Fondation pour la Recherche Médicale and CONICYT. CO holds a PhD scholarship from CONICYT, Chile. OK is supported by EMBO. AWEJ is a Medical Research Council student. We also thank Michael R Duchen (University College London) for the use of confocal facility (Zeiss LSM 510 Meta) and discussions, as well as to Dr. Roger Y Tsien (University of California at San Diego) for the donation of ERD1.

Funding

Acknowledgements. GK is supported by the Ligue Nationale contre le Cancer (équipe labellisée), European Commission (RIGHT, ChemoRes, Apop-Train, Apo-SYs), Agence Nationale pour la Recherche, Cancéropôle Ile-de-France and Institut National contre le Cancer (INCa). We thank the International Collaboration Program ECOS-CONICYT, project C08S01. JMV is supported by Fondation pour la Recherche Médicale and CONICYT. CO holds a PhD scholarship from CONICYT, Chile. OK is supported by EMBO. AWEJ is a Medical Research Council student. We also thank Michael R Duchen (University College London) for the use of confocal facility (Zeiss LSM 510 Meta) and discussions, as well as to Dr. Roger Y Tsien (University of California at San Diego) for the donation of ERD1.

Funders	Funder number
Cancéropôle Ile-de-France
European Commission
Agence Nationale de la Recherche
Comisión Nacional de Investigación Científica y Tecnológica
Fondation pour la Recherche Médicale
EMBO
Ligue Contre le Cancer
Right to Care

ASJC Scopus Subject Areas

Molecular Biology
Cell Biology

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10.1038/cdd.2009.34

Cite this

Vicencio, J. M., Ortiz, C., Criollo, A., Jones, A. W. E., Kepp, O., Galluzzi, L., Joza, N., Vitale, I., Morselli, E., Tailler, M., Castedo, M., Maiuri, M. C., Molgó, J., Szabadkai, G., Lavandero, S., & Kroemer, G. (2009). The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death and Differentiation, 16(7), 1006-1017. https://doi.org/10.1038/cdd.2009.34

Vicencio, JM, Ortiz, C, Criollo, A, Jones, AWE, Kepp, O, Galluzzi, L, Joza, N, Vitale, I, Morselli, E, Tailler, M, Castedo, M, Maiuri, MC, Molgó, J, Szabadkai, G, Lavandero, S & Kroemer, G 2009, 'The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1', Cell Death and Differentiation, vol. 16, no. 7, pp. 1006-1017. https://doi.org/10.1038/cdd.2009.34

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abstract = "The inositol 1,4,5-trisphosphate receptor (IP3R) is a major regulator of apoptotic signaling. Through interactions with members of the Bcl-2 family of proteins, it drives calcium (Ca2+) transients from the endoplasmic reticulum (ER) to mitochondria, thereby establishing a functional and physical link between these organelles. Importantly, the IP3R also regulates autophagy, and in particular, its inhibition/depletion strongly induces macroautophagy. Here, we show that the IP3R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed by the IP3 R and Beclin 1, an interaction that is increased or inhibited by overexpression or knockdown of Bcl-2, respectively. An effect of Beclin 1 on Ca2+ homeostasis was discarded as siRNA-mediated knockdown of Beclin 1 did not affect cytosolic or luminal ER Ca2+ levels. Xestospongin B- or starvation-induced autophagy was inhibited by overexpression of the IP3R ligand-binding domain, which coimmunoprecipitated with Beclin 1. These results identify IP3R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.",

author = "Vicencio, {J. M.} and C. Ortiz and A. Criollo and Jones, {A. W.E.} and O. Kepp and L. Galluzzi and N. Joza and I. Vitale and E. Morselli and M. Tailler and M. Castedo and Maiuri, {M. C.} and J. Molg{\'o} and G. Szabadkai and S. Lavandero and G. Kroemer",

note = "Funding Information: Acknowledgements. GK is supported by the Ligue Nationale contre le Cancer ({\'e}quipe labellis{\'e}e), European Commission (RIGHT, ChemoRes, Apop-Train, Apo-SYs), Agence Nationale pour la Recherche, Canc{\'e}rop{\^o}le Ile-de-France and Institut National contre le Cancer (INCa). We thank the International Collaboration Program ECOS-CONICYT, project C08S01. JMV is supported by Fondation pour la Recherche M{\'e}dicale and CONICYT. CO holds a PhD scholarship from CONICYT, Chile. OK is supported by EMBO. AWEJ is a Medical Research Council student. We also thank Michael R Duchen (University College London) for the use of confocal facility (Zeiss LSM 510 Meta) and discussions, as well as to Dr. Roger Y Tsien (University of California at San Diego) for the donation of ERD1.",

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AU - Vicencio, J. M.

AU - Ortiz, C.

AU - Criollo, A.

AU - Jones, A. W.E.

AU - Kepp, O.

AU - Galluzzi, L.

AU - Joza, N.

AU - Vitale, I.

AU - Morselli, E.

AU - Tailler, M.

AU - Castedo, M.

AU - Maiuri, M. C.

AU - Molgó, J.

AU - Szabadkai, G.

AU - Lavandero, S.

AU - Kroemer, G.

N1 - Funding Information: Acknowledgements. GK is supported by the Ligue Nationale contre le Cancer (équipe labellisée), European Commission (RIGHT, ChemoRes, Apop-Train, Apo-SYs), Agence Nationale pour la Recherche, Cancéropôle Ile-de-France and Institut National contre le Cancer (INCa). We thank the International Collaboration Program ECOS-CONICYT, project C08S01. JMV is supported by Fondation pour la Recherche Médicale and CONICYT. CO holds a PhD scholarship from CONICYT, Chile. OK is supported by EMBO. AWEJ is a Medical Research Council student. We also thank Michael R Duchen (University College London) for the use of confocal facility (Zeiss LSM 510 Meta) and discussions, as well as to Dr. Roger Y Tsien (University of California at San Diego) for the donation of ERD1.

PY - 2009

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N2 - The inositol 1,4,5-trisphosphate receptor (IP3R) is a major regulator of apoptotic signaling. Through interactions with members of the Bcl-2 family of proteins, it drives calcium (Ca2+) transients from the endoplasmic reticulum (ER) to mitochondria, thereby establishing a functional and physical link between these organelles. Importantly, the IP3R also regulates autophagy, and in particular, its inhibition/depletion strongly induces macroautophagy. Here, we show that the IP3R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed by the IP3 R and Beclin 1, an interaction that is increased or inhibited by overexpression or knockdown of Bcl-2, respectively. An effect of Beclin 1 on Ca2+ homeostasis was discarded as siRNA-mediated knockdown of Beclin 1 did not affect cytosolic or luminal ER Ca2+ levels. Xestospongin B- or starvation-induced autophagy was inhibited by overexpression of the IP3R ligand-binding domain, which coimmunoprecipitated with Beclin 1. These results identify IP3R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.

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The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1

Abstract

Bibliographical note

Funding

ASJC Scopus Subject Areas

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