Regulation of autophagy by the inositol trisphosphate receptor

The reduction of intracellular 1,4,5-inositol trisphosphate (IP₃) levels stimulates autophagy, whereas the enhancement of IP₃ levels inhibits autophagy induced by nutrient depletion. Here, we show that knockdown of the IP₃ receptor (IP₃R) with small interfering RNAs and pharmacological IP₃R blockade is a strong stimulus for the induction of autophagy. The IP₃R is known to reside in the membranes of the endoplasmic reticulum (ER) as well as within ER-mitochondrial contact sites, and IP₃R blockade triggered the autophagy of both ER and mitochondria, as exactly observed in starvation-induced autophagy. ER stressors such as tunicamycin and thapsigargin also induced autophagy of ER and, to less extent, of mitochondria. Autophagy triggered by starvation or IP₃R blockade was inhibited by Bcl-2 and Bcl-X_L specifically targeted to ER but not Bcl-2 or Bcl-X_L proteins targeted to mitochondria. In contrast, ER stress-induced autophagy was not inhibited by Bcl-2 and Bcl-X_L. Autophagy promoted by IP₃R inhibition could not be attributed to a modulation of steady-state Ca²⁺ levels in the ER or in the cytosol, yet involved the obligate contribution of Beclin-1, autophagy-related gene (Atg)5, Atg10, Atg12 and hVps34. Altogether, these results strongly suggest that IP₃R exerts a major role in the physiological control of autophagy.