Regulation of autophagy by the inositol trisphosphate receptor.

Full Abstract

The reduction of intracellular 1,4,5-inositol trisphosphate (IP(3)) levels stimulates autophagy, whereas the enhancement of IP(3) levels inhibits autophagy induced by nutrient depletion. Here, we show that knockdown of the IP(3) receptor (IP(3)R) with small interfering RNAs and pharmacological IP(3)R blockade is a strong stimulus for the induction of autophagy. The IP(3)R is known to reside in the membranes of the endoplasmic reticulum (ER) as well as within ER-mitochondrial contact sites, and IP(3)R 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 IP(3)R 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 IP(3)R inhibition could not be attributed to a modulation of steady-state Ca(2+) 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 IP(3)R exerts a major role in the physiological control of autophagy.

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Author information

Author/s: Criollo, A (A); Maiuri, M C (MC); Tasdemir, E (E); Vitale, I (I); Fiebig, A A (AA); Andrews, D (D); Molgó, J (J); Díaz, J (J); Lavandero, S (S); Harper, F (F); Pierron, G (G); di Stefano, D (D); Rizzuto, R (R); Szabadkai, G (G); Kroemer, G (G);

Affiliation: INSERM, U848, Institut Gustave Roussy, PR1 39 rue Camille Desmoulins, Villejuif, France.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Cell death and differentiation (Cell Death Differ), published in England. (Language: eng)

Reference: 2007-May; vol 14 (issue 5) : pp 1029-39

Dates: Created 2007/04/19; Completed 2007/05/23; Revised 2007/08/30;

PMID: 17256008, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: Autophagy. 2007 Jul-Aug;3(4):350-3. (PMID: 17404493)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Autophagy - genetics
Calcium - metabolism
Endoplasmic Reticulum - drug effects; metabolism
Food Deprivation
Hela Cells
Humans
Inositol 1,4,5-Trisphosphate - metabolism

Inositol 1,4,5-Trisphosphate - metabolism
Inositol 1,4,5-Trisphosphate Receptors - antagonists & inhibitors; metabolism
Macrocyclic Compounds - pharmacology
Mitochondria - drug effects; metabolism
Oxazoles - pharmacology
Protein Isoforms - metabolism
Rats
bcl-X Protein - metabolism

Associated Chemicals: Inositol 1,4,5-Trisphosphate Receptors (0) ; Macrocyclic Compounds (0) ; Oxazoles (0) ; Protein Isoforms (0) ; bcl-X Protein (0) ; Calcium (7440-70-2) ; Inositol 1,4,5-Trisphosphate (85166-31-0) ; xestospongin B (88840-01-1)

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