ARC, AN INHIBITOR OF APOPTOSIS EXPRESSED IN SKELETAL-MUSCLE AND HEARTTHAT INTERACTS SELECTIVELY WITH CASPASES

We have identified and characterized ARC, apoptosis repressor with cas pase recruitment domain (CARD), Sequence analysis revealed that ARC co ntains an N-terminal CARD used to a C-terminal region rich in proline/ glutamic acid residues. The CARD domain of ARC exhibited significant h omology to the prodomains of epical caspases and the CARDs present in the cell death regulators Apaf-1 and RAIDD. Immunoprecipitation analys is revealed that ARC interacts with caspase-2, -8, and Caenorhabditis elegans CED-3, but not with caspase-1, -3, or -9. ARC inhibited apopto sis induced by caspase-8 and CED-3 but not that mediated by caspase-9. Further analysis showed that the enzymatic activity of caspase-8 was inhibited by ARC in 293T cells. Consistent with the inhibition of casp ase-8, ARC attenuated apoptosis induced by FADD and TRADD and that tri ggered by stimulation of death receptors coupled to caspase 8, includi ng CD95/Fas, humor necrosis factor-Ri, and TRAMP/DR3. Remarkably, the expression of human ARC ias primarily restricted to skeletal muscle an d cardiac tissue. Thus, ARC represents an inhibitor of apoptosis expre ssed in muscle that appears to selectively target caspases. Delivery o f ARC by gene transfer or enhancement of its endogenous activity may p rovide a strategy for the treatment of diseases that are characterized by inappropriately increased cell death in muscle tissue.