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Caspase-1 is an apical caspase leading to caspase-3 cleavage in the AIM2 inflammasome response, independent of caspase-8


Sagulenko, V; Vitak, N; Vajjhala, P; Vince, JE; Stacey, KJ
2017-10-31
J Mol Biol
Journal Article in press
Canonical inflammasomes are multiprotein complexes that can activate both caspase-1 and caspase-8. Caspase-1 drives rapid lysis of cells by pyroptosis and maturation of IL-1beta and IL-18. In caspase-1-deficient cells, inflammasome formation still leads to caspase-3 activation and slower apoptotic death, dependent on caspase-8 as an apical caspase. A role for caspase-8 directly upstream of caspase-1 has also been suggested, but here we show that caspase-8-deficient macrophages have no defect in AIM2 inflammasome-mediated caspase-1 activation, pyroptosis and IL-1beta release. In investigating the inflammasome-induced apoptotic pathway, we previously demonstrated that activated caspase-8 is essential for caspase-3 cleavage and apoptosis in caspase-1-deficient cells. However, surprisingly, here we found that AIM2 inflammasome-initiated caspase-3 cleavage was maintained in Ripk3-/-Casp8-/- macrophages. Gene knockdown showed that caspase-1 was required for the caspase-3 cleavage. Thus inflammasomes activate a network of caspases that can promote both pyroptotic and apoptotic cell death. In cells where rapid pyroptosis is blocked, delayed inflammasome-dependent cell death could still occur due to both caspase-1- and caspase-8-dependent apoptosis. Initiation of redundant cell death pathways is likely to be a strategy for coping with pathogen interference in death processes.
Elsevier
Inflammation
10.1016/j.jmb.2017.10.028
29100888
Refer to copyright notice on published article.

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Creation Date 2017-11-29 08:57:58 Last Modified 2017-11-29 09:30:14