1. ¹INSERM, U848, Institut Gustave Roussy, PR1 39 rue Camille Desmoulins, Villejuif, France
2. ²Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France
3. ³Université Paris Sud, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France
4. ⁴FONDAP Center CEMC, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile
5. ⁵Department of Experimental Pharmacology, Faculty of Biotechnological Sciences, Università degli Studi di Napoli, Federico II, Italy
6. ⁶Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, CDN-Hamilton, Ontario, Canada
7. ⁷Centre National de la Recherche Scientifique, Institut de Neurobiologie Alfred Fessard, FRC2118, UPR 9040, Gif-sur-Yvette, France
8. ⁸CNRS, FRE 2937, Institut André Lwoff, Villejuif, France
9. ⁹Department of Experimental and Diagnostic Medicine and Interdisciplinary Center for the Study of Inflammation and ER-GenTech, University of Ferrara, Ferrara, Italy

Correspondence: G Kroemer, CNRS-UMR8125, Institut Gustave Roussy, PR1, 38 rue Camille Desmoulins, F-94805 Villejuif, France. Tel: +33 1 42116046; Fax: +33 1 42116047; E-mail: kroemer@igr.fr

Received 11 October 2006; Revised 5 December 2006; Accepted 13 December 2006; Published online 26 January 2007.

Abstract

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.