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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)1006-1017
Number of pages12
JournalCell Death and Differentiation
Volume16
Issue number7
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    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