RIPK1 Blocks Early Postnatal Lethality Mediated by Caspase-8 and RIPK3 (original) (raw)

“…Interestingly, even though RIPK1 was believed to be an essential mediator of RIPK3 activation, necroptosis can still be engaged with Ripk1 deletion. 80,81 Thus, necroptosis may be mediated through not only TAK1-RIPK1-RIPK3 complex but also through alternative complexes lacking either TAK1 or RIPK1. In summary, despite the fact that Tak1 deletion leads to hypersensitivity to TNFa-induced cell death (apoptosis), activation of TAK1 is also associated with TNFa-induced cell death (necroptosis).…”

Section: Tak1 As a Necroptosis Inducermentioning

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“…Interestingly, even though RIPK1 was believed to be an essential mediator of RIPK3 activation, necroptosis can still be engaged with Ripk1 deletion. 80,81 Thus, necroptosis may be mediated through not only TAK1-RIPK1-RIPK3 complex but also through alternative complexes lacking either TAK1 or RIPK1. In summary, despite the fact that Tak1 deletion leads to hypersensitivity to TNFa-induced cell death (apoptosis), activation of TAK1 is also associated with TNFa-induced cell death (necroptosis).…”

Section: Tak1 As a Necroptosis Inducermentioning

“…Two lines of evidence support the idea that necroptosis inhibits apoptosis: (1) inhibition of RIPK3 by expressing a kinase-dead version of RIPK3 is reported to cause apoptotic cell death in vivo, which results in blood vessel abnormalities similar to endothelial-specific deletion of Tak1; 37,97 (2) deletion of Ripk1 primarily induces apoptotic cell death and tissue injury in vivo, although necroptosis is also induced. 80,81 Thus, inhibition and/or deletion of any part of the necroptotic protein kinase cascade (TAK1, RIPK1 or RIPK3) activates apoptotic cell death in vivo. Based on these, we propose that apoptosis and necroptosis are reciprocally regulated ( Figure 4).…”

Section: Tak1mentioning

“…63,76,77 In addition, during development the physiological role of RIP1 in regulating RIP3-driven necroptosis appears to be highly dependent on the stage of development with RIP1 being required for TNF-induced necroptosis at E10.5 78 but inhibiting necroptosis and associated inflammation at later stages of development. 78,79 Although RIP3-driven necroptosis contributes to the perinatal defects associated with RIP1 deficiency, it is not the sole underlying mechanism. 63 This is supported by recent studies demonstrating an important role for RIP1 in protecting against TNF-and caspase 8-driven apoptosis.…”

Section: Rip1 and Rip3 As Drivers Of Necroptosismentioning

“…63 This is supported by recent studies demonstrating an important role for RIP1 in protecting against TNF-and caspase 8-driven apoptosis. 76,79 Under conditions of TNF stimulation, or during virus infection, that trigger RIP1-dependent necrosis, RIP3 promotes necrosis-specific phosphorylation of RIP1, thus forming a pro-necrotic necrosome complex. 62 Phosphorylation-induced activation of the necrosome is dependent on prior de-ubiquitination of RIP1 by CYLD, a step that is proposed to take place in the necrosome itself and not in Complex I.…”

Section: Rip1 and Rip3 As Drivers Of Necroptosismentioning

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