ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases.
We have identified and characterized ARC, apoptosis repressor with caspase recruitment domain (CARD). Sequence analysis revealed that ARC contains an N-terminal CARD fused to a C-terminal region rich in proline/glutamic acid residues. The CARD domain of ARC exhibited significant homology to the prodomains of apical caspases and the CARDs present in the cell death regulators Apaf-1 and RAIDD. Immunoprecipitation analysis revealed that ARC interacts with caspase-2, -8, and Caenorhabditis elegans CED-3, but not with caspase-1, -3, or -9. ARC inhibited apoptosis 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 caspase-8, ARC attenuated apoptosis induced by FADD and TRADD and that triggered by stimulation of death receptors coupled to caspase-8, including CD95/Fas, tumor necrosis factor-R1, and TRAMP/DR3. Remarkably, the expression of human ARC was primarily restricted to skeletal muscle and cardiac tissue. Thus, ARC represents an inhibitor of apoptosis expressed in muscle that appears to selectively target caspases. Delivery of ARC by gene transfer or enhancement of its endogenous activity may provide a strategy for the treatment of diseases that are characterized by inappropriately increased cell death in muscle tissue.
Koseki
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Departments of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Inohara
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N
Chen
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Núñez
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G
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000502:physiology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D011485:Protein Binding; D011506:Proteins / Q000502:physiology; D016415:Sequence Alignment; D047990:TNF Receptor-Associated Factor 1
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D009124:Muscle Proteins; C112246:NOL3 protein, human; D011506:Proteins; D047990:TNF Receptor-Associated Factor 1; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases