title: Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6.
abstract: Necroptosis is a form of programmed cell death that occurs in the absence of caspase activation and depends on the activity of the receptor-interacting protein kinases. Inactivation of these kinases by caspase-mediated cleavage has been shown to be essential for successful embryonic development, survival and activation of certain cell types. The initiator of extrinsic apoptosis, caspase-8, which has a pro-death as well as a pro-life function, has been assigned this role. In the present study we demonstrate that caspase-6, an executioner caspase, performs this role during apoptosis induced through the intrinsic pathway. In addition, we demonstrate that in the absence of caspase activity, intrinsic triggers of apoptosis induce the receptor-interacting-kinase-1-dependent production of pro-inflammatory cytokines. We show that ubiquitously expressed caspase-6 has a supporting role in apoptosis by cleaving this kinase, thus preventing production of inflammatory cytokines as well as inhibiting the necroptotic pathway. These findings shed new light on the regulation of necroptosis as well as cell death in an inflammatory environment wherein cells receive both intrinsic and extrinsic death signals.
authors.affiliation: Program of Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. b.j.vanraam@gmail.com
authors.forename: B J
authors.initials: BJ
authors.lastname: van Raam
authors.forename: D E
authors.initials: DE
authors.lastname: Ehrnhoefer
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
authors.forename: G S
authors.initials: GS
authors.lastname: Salvesen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053178:Caspase 6 / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505514:CASP6 protein, human; D053178:Caspase 6