Research ArticleCell death

Unique BIR domain sets determine inhibitor of apoptosis protein–driven cell death and NOD2 complex signal specificity

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Sci. Signal.  17 Jul 2018:
Vol. 11, Issue 539, eaao3964
DOI: 10.1126/scisignal.aao3964

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Structure-function specificity of IAP proteins

Inhibitor of apoptosis proteins (IAPs) are involved in regulating cell death and inflammation. As such, both gain and loss of IAP function are associated with various diseases, from cancer to immune disorders. Chirieleison et al. examined the functional redundancy and selectivity of IAP family members as conferred by their structural motifs. The authors found that at least one IAP protein was critical for cell survival and that the catalytic domain of each protein, which provides E3 ubiquitin ligase activity, is redundant among the proteins but that its positioning within a triplet of protein-protein interaction domains confers distinct signaling functions among the proteins. These findings have implications for drug development as well as our understanding of the pathogenesis of immune disorders caused by IAP loss.

Abstract

The mammalian IAPs, X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2), play pivotal roles in innate immune signaling and inflammatory homeostasis, often working in parallel or in conjunction at a signaling complex. IAPs direct both nucleotide-binding oligomerization domain-containing 2 (NOD2) signaling complexes and cell death mechanisms to appropriately regulate inflammation. Although it is known that XIAP is critical for NOD2 signaling and that the loss of cIAP1 and cIAP2 blunts NOD2 activity, it is unclear whether these three highly related proteins can compensate for one another in NOD2 signaling or in mechanisms governing apoptosis or necroptosis. This potential redundancy is critically important, given that genetic loss of XIAP causes both very early onset inflammatory bowel disease and X-linked lymphoproliferative syndrome 2 (XLP-2) and that the overexpression of cIAP1 and cIAP2 is linked to both carcinogenesis and chemotherapeutic resistance. Given the therapeutic interest in IAP inhibition and the potential toxicities associated with disruption of inflammatory homeostasis, we used synthetic biology techniques to examine the functional redundancies of key domains in the IAPs. From this analysis, we defined the features of the IAPs that enable them to function at overlapping signaling complexes but remain independent and functionally exclusive in their roles as E3 ubiquitin ligases in innate immune and inflammatory signaling.

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