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J. Biol. Chem. 278 (40): 38699-38706

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

The Polypeptide Chain-releasing Factor GSPT1/eRF3 Is Proteolytically Processed into an IAP-binding Protein*

Ramesh Hegde {ddagger}, Srinivasa M. Srinivasula {ddagger} §, Pinaki Datta {ddagger}, Muniswamy Madesh {ddagger}, Richard Wassell {ddagger}, ZhiJia Zhang {ddagger}, NaEun Cheong {ddagger}, Julie Nejmeh {ddagger}, Teresa Fernandes-Alnemri {ddagger}, Shin-ichi Hoshino ¶, and Emad S. Alnemri {ddagger} ||

{ddagger}Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan

Abstract: Smac/Diablo and HtrA2/Omi are inhibitors of apoptosis (IAP)-binding proteins released from the mitochondria of human cells during apoptosis and regulate apoptosis by liberating caspases from IAP inhibition. Here we describe the identification of a proteolytically processed isoform of the polypeptide chain-releasing factor GSPT1/eRF3 protein, which functions in translation, as a new IAP-binding protein. In common with other IAP-binding proteins, the processed GSPT1 protein harbors a conserved N-terminal IAP-binding motif (AKPF). Additionally, processed GSPT1 interacts biochemically with IAPs and could promote caspase activation, IAP ubiquitination and apoptosis. The IAP-binding motif of the processed GSPT1 is absolutely required for these activities. Our findings are consistent with a model whereby processing of GSPT1 into the IAP-binding isoform could potentiate apoptosis by liberating caspases from IAP inhibition, or target IAPs and the processed GSPT1 for proteasome-mediated degradation.

Received for publication March 27, 2003. Revision received July 7, 2003.

* This work was supported by National Institutes of Health Grants AG13487 and CA78890 (to E. S. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ A special fellow of the Leukemia and Lymphoma Society.

|| To whom correspondence should be addressed: Thomas Jefferson University, Kimmel Cancer Institute, Bluemle Life Sciences Building, Rm. 904, 233 S. 10th St., Philadelphia, PA 19107. Tel.: 215-503-4632; Fax: 215-923-1098; E-mail: E_Alnemri{at}

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