title: In TNF-stimulated cells, RIPK1 promotes cell survival by stabilizing TRAF2 and cIAP1, which limits induction of non-canonical NF-kappaB and activation of caspase-8.
abstract: RIPK1 is involved in signaling from TNF and TLR family receptors. After receptor ligation, RIPK1 not only modulates activation of both canonical and NIK-dependent NF-κB, but also regulates caspase-8 activation and cell death. Although overexpression of RIPK1 can cause caspase-8-dependent cell death, when RIPK1(-/-) cells are exposed to TNF and low doses of cycloheximide, they die more readily than wild-type cells, indicating RIPK1 has pro-survival as well as pro-apoptotic activities. To determine how RIPK1 promotes cell survival, we compared wild-type and RIPK1(-/-) cells treated with TNF. Although TRAF2 levels remained constant in TNF-treated wild-type cells, TNF stimulation of RIPK1(-/-) cells caused TRAF2 and cIAP1 to be rapidly degraded by the proteasome, which led to an increase in NIK levels. This resulted in processing of p100 NF-κB2 to p52, a decrease in levels of cFLIP(L), and activation of caspase-8, culminating in cell death. Therefore, the pro-survival effect of RIPK1 is mediated by stabilization of TRAF2 and cIAP1.
authors.affiliation: Department of Biochemistry and La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Gentle
authors.forename: W Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Evans
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bankovacki
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Cook
authors.forename: Nufail R
authors.initials: NR
authors.lastname: Khan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nachbur
authors.forename: James
authors.initials: J
authors.lastname: Rickard
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.forename: Maryline
authors.initials: M
authors.lastname: Moulin
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Lluis
authors.forename: Donia M
authors.initials: DM
authors.lastname: Moujalled
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D053181:Caspase 8; D003513:Cycloheximide; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C506251:Ripk1 protein, mouse; C505526:Casp8 protein, mouse