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

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.