Regulation of cytoplasmic stress granules by apoptosis-inducing factor.
Stress granules (SG) are dynamic cytoplasmic foci in which stalled translation initiation complexes accumulate. In conditions of acute cellular redox, stress cells manipulated to lose the expression of apoptosis-inducing factor (AIF) nucleate SG signature proteins (e.g. TIA-1, PABP1) more efficiently than AIF-positive controls. AIF also inhibited SG formation induced by the RasGAP-associated endoribonuclease G3BP. Retransfection of mouse AIF into cells subjected to human AIF-specific siRNA revealed that only AIF imported into mitochondria could repress SGs and that redox-active domains of AIF, which are dispensable for its apoptogenic action, were required for SG inhibition. In response to oxidative stress, AIF-negative cells were found to deplete non-oxidized glutathione more rapidly than AIF-expressing cells. Exogenous supplementation of glutathione inhibited SG formation elicited by arsenate or G3BP. Together, these data suggest that the oxidoreductase function of AIF is required for the maintenance of glutathione levels in stress conditions and that glutathione is a major regulator of SG.
CNRS-UMR8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif, France.
Céline
C
Candé
Nicola
N
Vahsen
Didier
D
Métivier
Hélène
H
Tourrière
Karim
K
Chebli
Carmen
C
Garrido
Jamal
J
Tazi
Guido
G
Kroemer
D000111:Acetylcysteine / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D001149:Arsenates / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism*; D004265:DNA Helicases; D005420:Flavoproteins / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D000075223:Poly-ADP-Ribose Binding Proteins; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology*; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D034741:RNA, Small Interfering / Q000378:metabolism
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D001149:Arsenates; D002352:Carrier Proteins; D005420:Flavoproteins; D008565:Membrane Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D034741:RNA, Small Interfering; C042431:S-ethyl glutathione; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases; D005978:Glutathione; C025657:arsenic acid; D000111:Acetylcysteine