The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein.
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.
Hegde
Ramesh
R
Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Srinivasula
Srinivasa M
SM
Datta
Pinaki
P
Madesh
Muniswamy
M
Wassell
Richard
R
Zhang
ZhiJia
Z
Cheong
NaEun
N
Nejmeh
Julie
J
Fernandes-Alnemri
Teresa
T
Hoshino
Shin-ichi
S
Alnemri
Emad S
ES
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D000939:Epitopes / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D010454:Peptide Termination Factors / Q000737:chemistry* / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D003574:Cytochrome c Group; D018076:DNA, Complementary; D000939:Epitopes; D009097:Multienzyme Complexes; D010454:Peptide Termination Factors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D025801:Ubiquitin; C087971:peptide-chain-release factor 3; D005982:Glutathione Transferase; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex