Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNalpha-induced apoptosis.
Interferons (IFNs) inhibit the growth of many different cell types by altering the expression of specific genes. IFNs activities are partly mediated by the 2'-5' oligoadenylates-RNase L RNA decay pathway. RNase L is an endoribonuclease requiring activation by 2'-5' oligoadenylates to cleave single-stranded RNA. Here, we present evidence that degradation of mitochondrial mRNA by RNase L leads to cytochrome c release and caspase 3 activation during IFNalpha-induced apoptosis. We identify and characterize the mitochondrial translation initiation factor (IF2mt) as a new partner of RNase L. Moreover, we show that specific inhibition of mitochondrial translation with chloramphenicol inhibits the IFNalpha-induced degradation of mitochondrial mRNA by RNase L. Finally, we demonstrate that overexpression of IF2mt in human H9 cells stabilizes mitochondrial mRNA, inhibits apoptosis induced by IFNalpha and partially reverses IFNalpha-cell growth inhibition. On the basis of our results, we propose a model describing how RNase L regulates mitochondrial mRNA stability through its interaction with IF2mt.
Le Roy
F
F
UMR 5535, Institut de Génétique Moléculaire de Montpellier, 1919 route de Mende, 349293 Montpellier, France.
Silhol
M
M
Salehzada
T
T
Bisbal
C
C
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004722:Endoribonucleases / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D014176:Protein Biosynthesis; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D000077278:RNA, Mitochondrial; D011994:Recombinant Proteins; D020798:Two-Hybrid System Techniques
D017931:DNA Primers; D039642:Eukaryotic Initiation Factors; D007370:Interferon Type I; C486735:MTIF2 protein, human; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D011994:Recombinant Proteins; D012313:RNA; D045304:Cytochromes c; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; C505407:CASP3 protein, human; D053148:Caspase 3