Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition.
Inhibitors of apoptosis (IAPs) inhibit caspases, thereby preventing proteolysis of apoptotic substrates. IAPs occlude the active sites of caspases to which they are bound and can function as ubiquitin ligases. IAPs are also reported to ubiquitinate themselves and caspases. Several proteins induce apoptosis, at least in part, by binding and inhibiting IAPs. Among these are the Drosophila melanogaster proteins Reaper (Rpr), Grim, and HID, and the mammalian proteins Smac/Diablo and Omi/HtrA2, all of which share a conserved amino-terminal IAP-binding motif. We report here that Rpr not only inhibits IAP function, but also greatly decreases IAP abundance. This decrease in IAP levels results from a combination of increased IAP degradation and a previously unrecognized ability of Rpr to repress total protein translation. Rpr-stimulated IAP degradation required both IAP ubiquitin ligase activity and an unblocked Rpr N terminus. In contrast, Rpr lacking a free N terminus still inhibited protein translation. As the abundance of short-lived proteins are severely affected after translational inhibition, the coordinated dampening of protein synthesis and the ubiquitin-mediated destruction of IAPs can effectively reduce IAP levels to lower the threshold for apoptosis.
Holley
Christopher L
CL
C370 LSRC, Research Drive, Box 3813, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Olson
Michael R
MR
Colón-Ramos
Daniel A
DA
Kornbluth
Sally
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D029721:Drosophila Proteins; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D009865:Oocytes / Q000166:cytology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D014176:Protein Biosynthesis / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein; D014982:Xenopus laevis
D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D010455:Peptides; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C086973:rpr protein, Drosophila