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Dillon CP , Balachandran S
StIKKing it to a death kinase: IKKs prevent TNF-α-induced cell death by phosphorylating RIPK1
Cytokine. 2016 Feb;78 :47-50
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Signaling pathways activated by the cytokine TNF-alpha are among the most intensively studied and well-understood in all mammalian biology. In a simplistic model, two primary signals emanate from the TNF-alpha receptor, one that activates cell survival via an NF-kappaB transcriptional response and a second that triggers cell death when cell survival signals are neutralized. The kinase RIPK1 participates in both these axes, and its poly-ubiquitylation was thought to represent the primary mechanism by which it toggles between survival versus death signaling. When RIPK1 is ubiquitylated, it acts non-enzymatically as an adaptor protein in IKK recruitment and subsequent NF-kappaB activation; when ubiquitylation of RIPK1 is prevented, it functions as a cell death kinase capable of triggering apoptosis or necroptosis. Bertrand and colleagues (Dondelinger et al., 2015) now demonstrate that phosphorylation of RIPK1 represents an additional mechanism by which this protein switches between its life and death duties. They show that both IKK-alpha and IKK-beta phosphorylate RIPK1, dampening its capacity to assemble the death effectors FADD and caspase 8 into a functional pro-apoptotic signalsome. These IKKs also protect against RIPK1-mediated necroptosis. Importantly, IKK-alpha/beta prevent RIPK1-driven cell death independently of NF-kappaB transcriptional responses. These findings identify phosphorylation of RIPK1 by IKKs as a new mechanism by which cell fate decisions downstream of TNFR1 are regulated.
Export Date: 3 December 2015 Comment Cytokine. 2016 Feb;78:47-50. doi: 10.1016/j.cyto.2015.10.014. Epub 2015 Nov 28.