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 c rosslinking. 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 s ingle base change from T to A at base 786), replacing isoleucine with asparagine, abolishes the signal transducing properly of Fas. Mice hom ozygous for this mutant allele (lpr(cg)/lpr(cg) mice) develop lymphade nopathy and a lupus-like autoimmune disease. Little is known about the mechanism of signal transduction in Fas-mediated apoptosis. In this s tudy, we used the two-hybrid screen in yeast to isolate a Fas-associat ed protein factor, FAF1, which specifically interacts with the cytopla smic domain of wild-type Fas but not the lpr(cg)-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 a poptosis. A search of available DNA and protein sequence data banks di d not reveal significant homology between FAF1 and known proteins. The refore, FAF1 is an unusual protein that binds to the wild type but not the inactive point mutant of Fas. FAF1 potentiates Fas-induced cell k illing and is a candidate signal transducing molecule in the regulatio n of apoptosis.