Sci. STKE, 7 October 2003
APOPTOSIS Cleaved GSPT1: A New IAP-Binding Protein
Inactivation or stimulated degradation of the inhibitor of apoptosis proteins (IAPs) constitutes one component of the apoptotic pathway. Proteins that have a conserved IAP-binding motif (IBM), which mediates the interaction with the BIR domains of IAPs, inhibit the antiapoptotic activity of IAPs. Hegde et al. identified GSTP1 (also known as eRF3) as a human IBM-containing protein on the basis of its ability to interact with a glutathione S-transferase (GST)-BIR fusion protein. GSTP1 is known as a G1-to-S-phase transition protein and as a protein that functions in translation. GST-BIR affinity purification identified a form of GSTP1 that was cleaved of the first 60 amino acids, which exposed an IBM domain. Only the processed GSTP1 was able to interact with GST-BIR and processed GSTP1 bound to full-length IAPs, XIAP, c-IAP1, and c-IAP2. In transfected cells, both the full-length and cleaved forms of GSTP1 were detectable, with the cleaved form representing a fraction of the total; thus, stimulation of GSTP1 cleavage may provide a point of regulation for the GSTP1 and IAP interaction. Cleaved GSTP1 stimulated caspase activity in vitro, and overexpression of cleaved GSTP1 led to increased cellular caspase activation and apoptosis. Immunostaining showed that full-length GSTP1 is predominantly localized to the endoplasmic reticulum and overexpression of the cleaved form of GSTP1 showed a cytosolic and nuclear localization, which suggests that cleavage of GSTP1 may alter the subcellular distribution of GSTP1. The enzyme responsible for GSTP1 processing to produce an IAP-binding protein and the signals that may regulate such processing remain to be determined.
R. Hegde, S. M. Srinivasula, P. Datta, M. Madesh, R. Wassell, Z. Zhang, N. Cheong, J. Nejmeh, T. Fernandes-Alnemri, S. Hoshino, E. S. Alnemri, The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein. J. Biol. Chem. 278, 38699-38706 (2003). [Abstract] [Full Text]
Citation: Cleaved GSPT1: A New IAP-Binding Protein. Sci. STKE 2003, tw396 (2003).
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