StIKKing it to a death kinase: IKKs prevent TNF-α-induced cell death by phosphorylating RIPK1.
Signaling pathways activated by the cytokine TNF-α are among the most intensively studied and well-understood in all mammalian biology. In a simplistic model, two primary signals emanate from the TNF-α receptor, one that activates cell survival via an NF-κB 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-κB 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-α and IKK-β 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-α/β prevent RIPK1-driven cell death independently of NF-κB transcriptional responses. These findings identify phosphorylation of RIPK1 by IKKs as a new mechanism by which cell fate decisions downstream of TNFR1 are regulated.
['Dillon|Christopher P|CP|', 'Balachandran|Siddharth|S|']
D000818:Animals D017209:Apoptosis D053181:Caspase 8 D016923:Cell Death D053200:Fas-Associated Death Domain Protein D005347:Fibroblasts D051550:I-kappa B Kinase D051379:Mice D016328:NF-kappa B D009336:Necrosis D010766:Phosphorylation D053422:Receptor-Interacting Protein Serine-Threonine Kinases D047888:Receptors, Tumor Necrosis Factor, Type I D015398:Signal Transduction D014409:Tumor Necrosis Factor-alpha D054875:Ubiquitination
IKK RIPK1 Apoptosis Necroptosis TNF