title: Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2.
abstract: 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.
authors.affiliation: Departments of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Csomos
authors.forename: Graham F
authors.initials: GF
authors.lastname: Brady
authors.forename: Colin S
authors.initials: CS
authors.lastname: Duckett
mesh_terms: 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
chemical_list: 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