The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein

Ramesh Hegde; Srinivasa M Srinivasula; Pinaki Datta; Muniswamy Madesh; Richard Wassell; ZhiJia Zhang; NaEun Cheong; Julie Nejmeh; Teresa Fernandes-Alnemri; Shin-ichi Hoshino; Emad S Alnemri

doi:10.1074/jbc.M303179200

The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein

J Biol Chem. 2003 Oct 3;278(40):38699-706. doi: 10.1074/jbc.M303179200. Epub 2003 Jul 15.

Authors

Ramesh Hegde¹, Srinivasa M Srinivasula, Pinaki Datta, Muniswamy Madesh, Richard Wassell, ZhiJia Zhang, NaEun Cheong, Julie Nejmeh, Teresa Fernandes-Alnemri, Shin-ichi Hoshino, Emad S Alnemri

Affiliation

¹ Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

PMID: 12865429
DOI: 10.1074/jbc.M303179200

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.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acid Motifs
Amino Acid Sequence
Apoptosis
Blotting, Western
Caspases / metabolism
Cell Line
Cloning, Molecular
Cysteine Endopeptidases / metabolism
Cytochrome c Group / metabolism
DNA, Complementary / metabolism
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Endoplasmic Reticulum / metabolism
Enzyme Activation
Epitopes / chemistry
Glutathione Transferase / metabolism
Humans
Microscopy, Confocal
Mitochondria / metabolism
Molecular Sequence Data
Multienzyme Complexes / metabolism
Peptide Termination Factors / chemistry*
Peptide Termination Factors / physiology*
Proteasome Endopeptidase Complex
Protein Binding
Protein Biosynthesis
Protein Isoforms
Protein Structure, Tertiary
Recombinant Proteins / metabolism
Sequence Homology, Amino Acid
Subcellular Fractions
Time Factors
Transfection
Tumor Cells, Cultured
Ubiquitin / metabolism

Substances

Cytochrome c Group
DNA, Complementary
Epitopes
Multienzyme Complexes
Peptide Termination Factors
Protein Isoforms
Recombinant Proteins
Ubiquitin
peptide-chain-release factor 3
Glutathione Transferase
Caspases
Cysteine Endopeptidases
Proteasome Endopeptidase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding