TY - JOUR
T1 - The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1
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
Y1 - 2009
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.
AB - 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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U2 - 10.1038/cdd.2009.34
DO - 10.1038/cdd.2009.34
M3 - Article
C2 - 19325567
AN - SCOPUS:67549135655
SN - 1350-9047
VL - 16
SP - 1006
EP - 1017
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 7
ER -