title: StIKKing it to a death kinase: IKKs prevent TNF-α-induced cell death by phosphorylating RIPK1.
abstract: 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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Dillon
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address: Siddharth.balachandran@fccc.edu.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000235:genetics; D016923:Cell Death; D053200:Fas-Associated Death Domain Protein / Q000235:genetics; D005347:Fibroblasts; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010766:Phosphorylation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D051550:I-kappa B Kinase; D053181:Caspase 8
keywords: Apoptosis; IKK; Necroptosis; RIPK1; TNF