title: 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.affiliation: INSERM, U848, F-94805 Villejuif, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Vicencio
authors.forename: C
authors.initials: C
authors.lastname: Ortiz
authors.forename: A
authors.initials: A
authors.lastname: Criollo
authors.forename: A W E
authors.initials: AW
authors.lastname: Jones
authors.forename: O
authors.initials: O
authors.lastname: Kepp
authors.forename: L
authors.initials: L
authors.lastname: Galluzzi
authors.forename: N
authors.initials: N
authors.lastname: Joza
authors.forename: I
authors.initials: I
authors.lastname: Vitale
authors.forename: E
authors.initials: E
authors.lastname: Morselli
authors.forename: M
authors.initials: M
authors.lastname: Tailler
authors.forename: M
authors.initials: M
authors.lastname: Castedo
authors.forename: M C
authors.initials: MC
authors.lastname: Maiuri
authors.forename: J
authors.initials: J
authors.lastname: Molgó
authors.forename: G
authors.initials: G
authors.lastname: Szabadkai
authors.forename: S
authors.initials: S
authors.lastname: Lavandero
authors.forename: G
authors.initials: G
authors.lastname: Kroemer