Abstract
The RIP kinases have emerged as essential mediators of cellular stress that integrate both extracellular stimuli emanating from various cell-surface receptors and signals coming from intracellular pattern recognition receptors. The molecular mechanisms regulating the ability of the RIP proteins to transduce the stress signals remain poorly understood, but seem to rely only partially on their kinase activities. Recent studies on RIP1 and RIP2 have highlighted the importance of ubiquitination as a key process regulating their capacity to activate downstream signaling pathways. In this study, we found that XIAP, cIAP1 and cIAP2 not only directly bind to RIP1 and RIP2 but also to RIP3 and RIP4. We show that cIAP1 and cIAP2 are direct E3 ubiquitin ligases for all four RIP proteins and that cIAP1 is capable of conjugating the RIPs with diverse types of ubiquitin chains, including linear chains. Consistently, we show that repressing cIAP1/2 levels affects the activation of NF-κB that is dependent on RIP1, -2, -3 and -4. Finally, we identified Lys51 and Lys145 of RIP4 as two critical residues for cIAP1-mediated ubiquitination and NF-κB activation.
Highlights
Cells are continuously confronted with stress signals that initiate at the cell surface or within the cell
The SMAC binding site of the BIR2 domain of XIAP was shown to be crucial for RIP2 binding, and the association of XIAP with RIP2 could be inhibited in presence of a SMAC mimetic compound [40]
Among the eight Inhibitor of apoptosis proteins (IAPs) members encoded by the human genome, five contain a carboxy-terminal RING domain that provides them with E3 ubiquitin ligase activity, and two were shown to regulate RIP1 and RIP2 functions by conjugating them with ubiquitin chains[28,29,30,31]
Summary
Cells are continuously confronted with stress signals that initiate at the cell surface or within the cell. The ability to transduce the signal and to activate a cellular response, either through transcription-dependent or –independent mechanisms, relies on the recruitment of adaptor proteins to the extra- and intra-cellular sensors. Among these adaptors, members of the receptor-interacting protein kinase (RIP) family have emerged as essential mediators of cellular stress. RIP1, the first identified member of the RIP kinase family, was shown to participate in the signaling pathways activated downstream of several members of the TNF receptor superfamily[2], Toll-like receptors (TLR) 3 and 4[2,3], and after genotoxic stress[4]. RIP1 can mediate gene transcription through activation of the MAPK and NF-kB signaling pathways, and can induce cell death by the formation of death complexes. Transgenic studies have indicated that this kinase plays a role in proper skin development and inflammatory responses[18,19]
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