Inhibition of macroautophagy triggers apoptosis.
Mammalian cells were observed to die under conditions in which nutrients were depleted and, simultaneously, macroautophagy was inhibited either genetically (by a small interfering RNA targeting Atg5, Atg6/Beclin 1-1, Atg10, or Atg12) or pharmacologically (by 3-methyladenine, hydroxychloroquine, bafilomycin A1, or monensin). Cell death occurred through apoptosis (type 1 cell death), since it was reduced by stabilization of mitochondrial membranes (with Bcl-2 or vMIA, a cytomegalovirus-derived gene) or by caspase inhibition. Under conditions in which the fusion between lysosomes and autophagosomes was inhibited, the formation of autophagic vacuoles was enhanced at a preapoptotic stage, as indicated by accumulation of LC3-II protein, ultrastructural studies, and an increase in the acidic vacuolar compartment. Cells exhibiting a morphology reminiscent of (autophagic) type 2 cell death, however, recovered, and only cells with a disrupted mitochondrial transmembrane potential were beyond the point of no return and inexorably died even under optimal culture conditions. All together, these data indicate that autophagy may be cytoprotective, at least under conditions of nutrient depletion, and point to an important cross talk between type 1 and type 2 cell death pathways.
Boya
Patricia
P
CNRS-UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France. kroemer@igr.fr.
González-Polo
Rosa-Ana
RA
Casares
Noelia
N
Perfettini
Jean-Luc
JL
Dessen
Philippe
P
Larochette
Nathanael
N
Métivier
Didier
D
Meley
Daniel
D
Souquere
Sylvie
S
Yoshimori
Tamotsu
T
Pierron
Gérard
G
Codogno
Patrice
P
Kroemer
Guido
G
D000225:Adenine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008985:Monensin / Q000633:toxicity; D010588:Phagosomes / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C420323:UL37 protein, Human herpesvirus 5; D014764:Viral Proteins; C025946:3-methyladenine; D008985:Monensin; D020169:Caspases; D000225:Adenine