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-XL specifically targeted to ER but not Bcl-2 or Bcl-XL proteins targeted to mitochondria. In contrast, ER stress- induced autophagy was not inhibited by Bcl-2 and Bcl- XL. 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.