The inositol trisphosphate receptor in the control of autophagy

The second messenger myo-inositol-1,4,5-trisphosphate (IP3) acts on the IP3 receptor (IP3R), an IP3-activated Ca2+ channel of the endoplasmic reticulum (ER). The IP3R agonist IP3 inhibits starvation-induced autophagy. The IP3R antagonist xestospongin B induces autophagy in human cells through a pathway that requires the obligate contribution of Beclin-1, Atg5, Atg10, Atg12 and hVps34, yet is inhibited by ER-targeted Bcl-2 or Bcl-X-L, two proteins that physically interact with IP3R. Autophagy can also be induced by depletion of the IP3R by small interfering RNAs. Autophagy induction by IP3R blockade cannot be explained by changes in steady state levels of Ca2+ in the endoplasmic reticulum (ER) and the cytosol. Autophagy induction by IP3R blockade is effective in cells lacking the obligate mediator of ER stress IRE1. In contrast, IRE1 is required for autophagy induced by ER stress-inducing agents such a tunicamycin or thapsigargin. These findings suggest that there are several distinct pathways through which autophagy can be initiated at the level of the ER.