Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2.
Inhibitor of apoptosis (IAP) proteins are key regulators of intracellular signaling that interact with tumor necrosis factor (TNF) receptor superfamily members as well as proapoptotic molecules such as Smac/DIABLO and caspases. Whereas the X-linked IAP is an established caspase inhibitor, the protective mechanisms utilized by the cellular IAP (c-IAP) proteins are less clear because c-IAPs bind to but do not inhibit the enzymatic activities of caspases. In this study, c-IAPs are shown to be highly unstable molecules that undergo autoubiquitination. The autoubiquitination of c-IAP1 is blocked upon coexpression with TNF receptor-associated factor (TRAF) 2, and this is achieved by inhibition of the E3 ubiquitin ligase activity intrinsic to the RING of c-IAP1. Consistent with these observations, loss of TRAF2 results in a decrease in c-IAP1 levels. Stabilized c-IAP1 was found to sequester and prevent Smac/DIABLO from antagonizing X-linked IAP and protect against cell death. Therefore, this study describes an intriguing cytoprotective mechanism utilized by c-IAP1 and provides critical insight into how IAP proteins function to alter the apoptotic threshold.
Csomos
Rebecca A
RA
Departments of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Brady
Graham F
GF
Duckett
Colin S
CS
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D019610:Cytoprotection; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000378:metabolism*; D054875:Ubiquitination; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D047992:TNF Receptor-Associated Factor 2; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein