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

Abstract

The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a major regulator of apoptotic signaling. Through interactions with members of the Bcl-2 family of proteins, it drives calcium (Ca(2+)) transients from the endoplasmic reticulum (ER) to mitochondria, thereby establishing a functional and physical link between these organelles. Importantly, the IP(3)R also regulates autophagy, and in particular, its inhibition/depletion strongly induces macroautophagy. Here, we show that the IP(3)R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed by the IP(3)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 Ca(2+) homeostasis was discarded as siRNA-mediated knockdown of Beclin 1 did not affect cytosolic or luminal ER Ca(2+) levels. Xestospongin B- or starvation-induced autophagy was inhibited by overexpression of the IP(3)R ligand-binding domain, which coimmunoprecipitated with Beclin 1. These results identify IP(3)R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.

• Authors: 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
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 16 Issue 7 Pg. 1006-17 (Jul 2009) ISSN: 1476-5403 [Electronic] England
• PMID: 19325567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Inositol 1,4,5-Trisphosphate Receptors
• MAP1LC3A protein, human
• Macrocyclic Compounds
• Membrane Proteins
• Microtubule-Associated Proteins
• Oxazoles
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• xestospongin B
• Calcium

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (drug effects, physiology)
• Beclin-1
• Calcium (metabolism)
• Cell Line
• Cell Line, Tumor
• Gene Knockdown Techniques
• HeLa Cells
• Humans
• Inositol 1,4,5-Trisphosphate Receptors (antagonists & inhibitors, metabolism)
• Macrocyclic Compounds (pharmacology)
• Membrane Proteins (genetics, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Oxazoles (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Rats