A Fas-associated protein factor, FAF1, potentiates Fas-mediated apoptosis.
Fas, a member of the tumor necrosis factor receptor family, can induce apoptosis when activated by Fas ligand binding or anti-Fas antibody crosslinking. Genetic studies have shown that a defect in Fas-mediated apoptosis resulted in abnormal development and function of the immune system in mice. A point mutation in the cytoplasmic domain of Fas (a single base change from T to A at base 786), replacing isoleucine with asparagine, abolishes the signal transducing property of Fas. Mice homozygous for this mutant allele (lprcg/lprcg mice) develop lymphadenopathy and a lupus-like autoimmune disease. Little is known about the mechanism of signal transduction in Fas-mediated apoptosis. In this study, we used the two-hybrid screen in yeast to isolate a Fas-associated protein factor, FAF1, which specifically interacts with the cytoplasmic domain of wild-type Fas but not the lprcg-mutated Fas protein. This interaction occurs not only in yeast but also in mammalian cells. When transiently expressed in L cells, FAF1 potentiated Fas-induced apoptosis. A search of available DNA and protein sequence data banks did not reveal significant homology between FAF1 and known proteins. Therefore, FAF1 is an unusual protein that binds to the wild type but not the inactive point mutant of Fas. FAF1 potentiates Fas-induced cell killing and is a candidate signal transducing molecule in the regulation of apoptosis.
Department of Medicine, University of California, San Francisco 94143, USA.
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Williams
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003432:Cross-Linking Reagents; D004249:DNA Damage; D047908:Intracellular Signaling Peptides and Proteins; D007739:L Cells; D051379:Mice; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014162:Transfection; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015704:CD4 Antigens; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; C097186:Faf1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D019014:fas Receptor