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(Un)expected roles of c-IAPs in apoptotic and NFκB signaling pathways

Eugene Varfolomeev and Domagoj Vucic

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A family of anti-apoptotic regulators known as inhibitor of apoptosis (IAP) proteins block cell death in response to diverse stimuli. In spite of the fact that cellular IAP1and 2 (c IAP1 and 2) were discovered more than 12 years ago, their physiological roles have remained obscure. Several molecular mechanisms were proposed to explain their anti-apoptotic activity, ranging from direct inhibition and ubiquitination of pro-apoptotic molecules, to the activation of pro-survival signaling. New findings present a surprising and complex twists. On the one hand, c IAP1 and c IAP2 suppress Tumor Necrosis Factor α (TNFα) stimulated cell death by preventing formation of the TNF Receptor 1 (TNFR1) pro-apoptotic signaling complex. On the other hand, they regulate pro-survival NFκB signaling pathways: in the non-canonical pathway, by ubiquitination of NFκB-inducing kinase (NIK), and in the canonical pathway, by a yet-to-be-defined mechanism. In addition, c IAPs self-regulate their protein levels through RING domain mediated auto-ubiquitination. Here, we discuss the most recent progress in our understanding of the biological roles of c-IAPs, as well as the implications of targeting c IAPs for therapeutic intervention.

Authors

Eugene Varfolomeev

Genentech, Inc.; South San Francisco, CA

Domagoj Vucic

Genentech, Inc.; South San Francisco, CA

Purchase article for $19

Subscribe to this journal for $129/year