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

Overview

MeSH Major

  • Apoptosis Regulatory Proteins
  • Autophagy
  • Inositol 1,4,5-Trisphosphate Receptors
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins c-bcl-2

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.

publication date

  • March 30, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/cdd.2009.34

PubMed ID

  • 19325567

Additional Document Info

start page

  • 1006

end page

  • 17

volume

  • 16

number

  • 7