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Regulation of Autophagy by the Inositol Trisphosphate Receptor

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Regulation of Autophagy by the Inositol Trisphosphate Receptor Cell Death and Differentiation (2007) 14, 1029–1039 & 2007 Nature Publishing Group All rights reserved 1350-9047/07 $30.00 www.nature.com/cdd Regulation of autophagy by the inositol trisphosphate receptor A Criollo1,2,3,4, MC Maiuri1,2,5, E Tasdemir1,2,3, I Vitale1,2,3, AA Fiebig6, D Andrews6, J Molgo´ 7,JDı´az4, S Lavandero4, F Harper8, G Pierron8, D di Stefano9, R Rizzuto9, G Szabadkai9 and G Kroemer*,1,2,3 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 þ 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. Cell Death and Differentiation (2007) 14, 1029–1039. doi:10.1038/sj.cdd.4402099; published online 26 January 2007 The first step of macroautophagy consists in the gradual human cell lines cultured in nutrient-free media mount a envelopment of cytoplasmic material (cytosol and/or orga- cytoprotective autophagic response. Suppression of auto- nelles) in the phagophore, a cistern that finally sequesters phagy by chemical inhibitors or knockdown of essential genes cytoplasmic material in autophagosomes (also called auto- thus sensitize cells to starvation-induced cell death.6,7 phagic vacuoles (AVs)) lined by two membranes. Autophago- Autophagy inhibition also sensitizes cells to the depletion of somes then undergo a progressive maturation by fusion with obligatory growth (or survival) factors resulting in a decrease endosomes and/or lysosomes. This latter step creates of nutrient import through the plasma membrane. For autolysosomes in which the inner membrane as well as the example, the knockdown of Atg5, Atg10 or Atg12 (which are luminal content of the AVs is degraded by lysosomal all involved in a ubiquitin-like conjugation system required enzymes. The process of autophagy is controlled by a series for autophagosome formation) prevents the generation of AV of evolutionary conserved genes, the atg genes, whose and sensitizes cells to cell death induced by withdrawal of products are essential for specific steps of the autophagic essential growth factors.8 Similarly, knockdown of Atg6/ process.1,2 Beclin-1 (whose major physiological partner is the class III One of the strongest triggers of autophagy is nutrient phosphatidylinositol 3- kinase Vps34) inhibits autophagy and stress.3,4 In response to starvation, cells degrade nonessen- sensitizes to cell death induced by starvation.6,8 Beclin-1 also tial components thereby generating nutrients for meeting interacts with Bcl-2,9 which inhibits autophagy,10 perhaps by the cell’s energetic demand as well as for vital biosynthetic preventing the interaction between Beclin-1 and Vps34.11 reactions. In such circumstances, when autophagy is an One recent study suggested that myo-inositol-1,4,5-tris- adaptation, inhibition of autophagy has a negative impact on phosphate (IP3) could regulate autophagy because inhibition cell survival. For example, mice lacking the atg5 gene survive of inositol monophosphatase by lithium or L-690,330 stimu- 12 without any major developmental defect until birth, yet lates autophagy through the depletion of inositol and IP3. IP3 succumb to the stressful neonatal period unless puppies are is a second messenger produced primarily in response to the force-fed with milk within the first hours after birth.5 Similarly, stimulation of G-protein-coupled receptor or receptor tyrosine 1INSERM, U848, Institut Gustave Roussy, PR1 39 rue Camille Desmoulins, Villejuif, France; 2Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France; 3Universite´ Paris Sud, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France; 4FONDAP Center CEMC, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile; 5Department of Experimental Pharmacology, Faculty of Biotechnological Sciences, Universita` degli Studi di Napoli, Federico II, Italy; 6Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, CDN-Hamilton, Ontario, Canada; 7Centre National de la Recherche Scientifique, Institut de Neurobiologie Alfred Fessard, FRC2118, UPR 9040, Gif-sur-Yvette, France; 8CNRS, FRE 2937, Institut Andre´ Lwoff, Villejuif, France and 9Department of Experimental and Diagnostic Medicine and Interdisciplinary Center for the Study of Inflammation and ER-GenTech, University of Ferrara, Ferrara, Italy *Corresponding author: G Kroemer, CNRS-UMR8125, Institut Gustave Roussy, PR1, 38 rue Camille Desmoulins, F-94805 Villejuif, France. Tel: þ 33 1 42116046; Fax: þ 33 1 42116047; E-mail: [email protected] Keywords: apoptosis; Bcl-2; autophagic vacuoles; endoplasmic reticulum; mitochondria Abbreviations: Atg, autophagy-related gene; AV, autophagic vacuole; ER, endoplasmic reticulum; IP3, 1,4,5-inositol trisphosphate; IP3R, IP3 receptor; DCm, mitochondrial transmembrane potential; PI, propidium iodine Received 11.10.06; revised 05.12.06; accepted 13.12.06; Edited by M Piacentini; published online 26.1.07 IP3R in autophagy A Criollo et al 1030 kinases. IP3 acts on the IP3 receptor (IP3R), a mostly ER stress-induced autophagy affects ER and endoplasmic reticulum (ER)-sessile Ca2 þ release channel mitochondria. ER stress triggered the emergence of bona that integrates signals from numerous small molecules and fide AVs, as defined by cytoplasmic structures lined by two proteins including nucleotides, kinases and phosphatases, as membranes that can be detected by transmission electron 13 well as nonenzyme proteins. IP3R is known to play a major microscopy (Figure 2d and e). The LC3-GFP-positive role within the Ca2 þ microdomains that transmit Ca2 þ spikes vesicles induced by thapsigargin or tunicamycin colocalized 14,15 generated by the ER to mitochondria. IP3R is also with the ER marker calreticulin, but also colocalized in part 16,17 18 2 þ regulated by Bcl-2 and Bcl-XL, which affect Ca with the mitochondrial matrix marker HSP60, suggesting that fluxes through IP3R by direct molecular interactions, by ER stress causes autophagy of both ER and mitochondria influencing its regulatory phosphorylation and/or by modula- (Figure 2f–h). ER stress-induced autophagy followed a ting its response to IP3. Through these regulatory mecha- classical autophagic pathway to the extent that the nisms, IP3R modulates diverse cellular functions, which knockdown of essential atg genes such as atg6/beclin-1, include, but are not limited to, contraction/excitation, gene atg5, atg10, atg12 as well as the knockdown of the expression, cellular growth and apoptosis.13,19 mammalian class III phosphatidylinositol 3-kinase vps34 On the basis of these premises, we decided to investigate inhibited autophagy induced by thapsigargin, tunicamycin the contribution of IP3R to the regulation of autophagy. Here, or brefeldin A (Figure 3). Altogether, these data suggest that we report that the depletion of IP3R or its inhibition triggers ER stress effectively trigger autophagy that follows a rapid autophagy affecting both ER and mitochondria. IP3R canonical pathway. functions as a Bcl-2-regulated repressor of autophagy. IP3 depletion and IP3R inhibition stimulates autophagy of both ER and mitochondria. The inositol mono- Results and Discussion phosphatase inhibitors L-690,330 and lithium both induced autophagy (Figure 4a and b) under conditions in which Starvation-induced autophagy concerns both ER and neither agent induced toxic effects on the viability or bio- mitochondria. Upon 12 h of culture in the absence of energetic state of cells (Figure 4c). Both L-690,330 and serum and nutrients (starvation), HeLa cells manifest the lithium triggered significant autophagy of both ER and relocalization of LC3-GFP into AVs and this effect is inhibited mitochondria (Figure 4d–f). Very similar results were by addition of the cell-permeable IP3 precursor myo-inositol obtained by inhibition of IP3R. Knockdown of the IP3R I and (Figure 1a and b). Under these conditions, little cell death (as III isoforms caused a strong, nonsynergistic induction of determined with the vital dye propidium iodine (PI)) occurred autophagy, as measured by LC3-GFP relocalization (Figure after serum withdrawal and the reduction of the mitochondrial 5a and b). Similarly, xestospongin B, a chemical antagonist 26 transmembrane potential (DCm) induced by starvation was of IP3R, caused LC3-GFP aggregation in cytoplasmic inhibited by myo-inositol (Figure 1c). Starvation-induced vacuoles (Figure 5c). Stimulation
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