title: The inositol trisphosphate receptor in the control of autophagy.
abstract: The second messenger myo-inositol-1,4,5-trisphosphate (IP(3)) acts on the IP(3) receptor (IP(3)R), an IP(3)-activated Ca(2+) channel of the endoplasmic reticulum (ER). The IP(3)R agonist IP(3) inhibits starvation-induced autophagy. The IP(3)R antagonist xestospongin B induces autophagy in human cells through a pathway that requires the obligate contribution of Beclin-1, Atg5, Atg10, Atg12 and hVps34, yet is inhibited by ER-targeted Bcl-2 or Bcl-XL, two proteins that physically interact with IP(3)R. Autophagy can also be induced by depletion of the IP(3)R by small interfering RNAs. Autophagy induction by IP(3)R blockade cannot be explained by changes in steady state levels of Ca(2+) in the endoplasmic reticulum (ER) and the cytosol. Autophagy induction by IP(3)R blockade is effective in cells lacking the obligate mediator of ER stress IRE1. In contrast, IRE1 is required for autophagy induced by ER stress-inducing agents such a tunicamycin or thapsigargin. These findings suggest that there are several distinct pathways through which autophagy can be initiated at the level of the ER.
authors.affiliation: INSERM, U848, Villejuif, France.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vicencio
authors.forename: Ezgi
authors.initials: E
authors.lastname: Tasdemir
authors.forename: M Chiara
authors.initials: MC
authors.lastname: Maiuri
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001343:Autophagy / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005508:Food Deprivation; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008954:Models, Biological; D010080:Oxazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D034741:RNA, Small Interfering; D014415:Tunicamycin; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; C078549:xestospongin B