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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.

SUBMITTER: van Raam BJ

PROVIDER: S-EPMC3524638 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6.

van Raam B J BJ Ehrnhoefer D E DE Hayden M R MR Salvesen G S GS

Cell death and differentiation 20120803 1

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 ...[more]

PMID: 22858542

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Project description:Wound healing consists of a complex, dynamic and overlapping process involving inflammation, proliferation and tissue remodeling. A better understanding of wound healing process at the molecular level is needed for the development of novel therapeutic strategies. Receptor-interacting protein kinase 3 (RIPK3) controls programmed necrosis in response to TNF-α during inflammation and has been shown to be highly induced during cutaneous wound repair. However, its role in wound healing remains to be demonstrated. To study this, we created dorsal cutaneous wounds on male wild-type (WT) and RIPK3-deficient (Ripk3-/-) mice. Wound area was measured daily until day 14 post-wound and skin tissues were collected from wound sites at various days for analysis. The wound healing rate in Ripk3-/- mice was slower than the WT mice over the 14-day course; especially, at day 7, the wound size in Ripk3-/- mice was 53% larger than that of WT mice. H&E and Masson-Trichrome staining analysis showed impaired quality of wound closure in Ripk3-/- wounds with delayed re-epithelialization and angiogenesis and defected granulation tissue formation and collagen deposition compared to WT. The neutrophil infiltration pattern was altered in Ripk3-/- wounds with less neutrophils at day 1 and more neutrophils at day 3. This altered pattern was also reflected in the differential expression of IL-6, KC, IL-1β and TNF-α between WT and Ripk3-/- wounds. MMP-9 protein expression was decreased with increased Timp-1 mRNA in the Ripk3-/- wounds compared to WT. The microvascular density along with the intensity and timing of induction of proangiogenic growth factors VEGF and TGF-β1 were also decreased or delayed in the Ripk3-/- wounds. Furthermore, mouse embryonic fibroblasts (MEFs) from Ripk3-/- mice migrated less towards chemoattractants TGF-β1 and PDGF than MEFs from WT mice. These results clearly demonstrate that RIPK3 is an essential molecule to maintain the temporal manner of the normal progression of wound closure.

Dataset Information

Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6.

Publications

Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6.

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