Scythe regulates apoptosis-inducing factor stability during endoplasmic reticulum stress-induced apoptosis.
Scythe (BAT3; HLA-B associated transcript 3, Bag 6) is a protein that has been implicated in apoptosis because it can modulate the Drosophila melanogaster apoptotic regulator, Reaper. Mice lacking Scythe show pronounced defects in organogenesis and in the regulation of apoptosis and proliferation during mammalian development. However, the biochemical pathways important for Scythe function are unknown. We report here multiple levels of interaction between Scythe and the apoptogenic mitochondrial intermembrane protein AIF (apoptosis-inducing factor). Scythe physically interacts with AIF and regulates its stability. AIF stability is markedly reduced in Scythe(-/-) cells, which are more resistant to endoplasmic reticulum stress induced by thapsigargin. Reintroduction of Scythe or overexpression of AIF in Scythe(-/-) cells restores their sensitivity to apoptosis. Together, these data implicate Scythe as a regulator of AIF.
Desmots
Fabienne
F
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; UMR 6026, CNRS, Université de Rennes 1, 35042 Rennes Cedex, France. Electronic address: fabienne.desmots@univ-rennes1.fr.
Russell
Helen R
HR
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Michel
Denis
D
UMR 6026, CNRS, Université de Rennes 1, 35042 Rennes Cedex, France.
McKinnon
Peter J
PJ
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000737:chemistry* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
D051033:Apoptosis Inducing Factor; C092009:BAG6 protein, human; C484266:Bag6 protein, mouse; D002352:Carrier Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011506:Proteins