Abstract
SummaryTumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1’s cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.
Highlights
Inflammation and cell death are ancient processes of fundamental biological importance that enable survival and adaptation during infection and injury
Multivalent Interactions between cellular inhibitor of apoptosis 1 (cIAP1) and TRAF2 The BIR1 and RING domains of cIAP1/2 are required for Tumor necrosis factor (TNF) signaling, but little is known about the role of the UBA domain
While previous work established that TRAF2 binds to the BIR1 of cIAP1 and cIAP2 (Samuel et al, 2006; Vince et al, 2009; Zheng et al, 2010) (Figure 1A), our data suggest that TRAF2 associates with the C-terminal portion of cIAP1
Summary
Inflammation and cell death are ancient processes of fundamental biological importance that enable survival and adaptation during infection and injury. Upon TNF ligation, a protein complex assembles on the cytoplasmic tail of TNFR1 This complex, frequently referred to as complex-I, consists of TNF-R1, the adaptors TRADD and TRAF2, the kinase RIPK1, and the E3 ubiquitin (Ub) ligases cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2 (Silke, 2011; Ting and Bertrand, 2016). Within this complex, RIPK1 and other proteins are rapidly conjugated with M1, K11, K48, and K63 Ub linkage types (Dondelinger et al, 2016; Dynek et al, 2010; Gerlach et al, 2011; Peltzer et al, 2016), and cIAP-mediated conjugation of Ub to RIPK1 allows recruitment of the kinase complex TAK1/TAB2/TAB3 and the E3 ligase linear Ub chain assembly complex (LUBAC, composed of HOIL/HOIP/SHARPIN). While the synthesis of M1- and K63linked poly-Ub chains play key roles in Ub-dependent assembly of complex-I and the induction of NF-kB target genes that drive inflammation and cell survival following TNF stimulation, the role of K11 and K48 poly-Ub remains largely uncharacterized
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