RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation

Tran, HT; Kratina, T; Coutansais, A; Michalek, D; Hogan, BM; Lawlor, KE; Vince, JE; Silke, J; Lalaoui, N

Author(s): Tran, HT; Kratina, T; Coutansais, A; Michalek, D; Hogan, BM; Lawlor, KE; Vince, JE; Silke, J; Lalaoui, N;
Details: Publication Year 2024-03-21,Volume 31,Issue #5,Page 662-671
Journal Title: Cell Death & Differentiation
Abstract: Caspase-8 activity is required to inhibit necroptosis during embryogenesis in mice. In vitro studies have suggested that caspase-8 directly cleaves RIPK1, CYLD and the key necroptotic effector kinase RIPK3 to repress necroptosis. However, recent studies have shown that mice expressing uncleavable RIPK1 die during embryogenesis due to excessive apoptosis, while uncleavable CYLD mice are viable. Therefore, these results raise important questions about the role of RIPK3 cleavage. To evaluate the physiological significance of RIPK3 cleavage, we generated Ripk3(D333A/D333A) mice harbouring a point mutation in the conserved caspase-8 cleavage site. These mice are viable, demonstrating that RIPK3 cleavage is not essential for blocking necroptosis during development. Furthermore, unlike RIPK1 cleavage-resistant cells, Ripk3(D333A/D333A) cells were not significantly more sensitive to necroptotic stimuli. Instead, we found that the cleavage of RIPK3 by caspase-8 restricts NLRP3 inflammasome activation-dependent pyroptosis and IL-1β secretion when Inhibitors of APoptosis (IAP) are limited. These results demonstrate that caspase-8 does not inhibit necroptosis by directly cleaving RIPK3 and further underscore a role for RIPK3 in regulating the NLRP3 inflammasome.
Publisher: Springer Nature
Keywords: Animals; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism; *Necroptosis; *Inflammasomes/metabolism; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; *Caspase 8/metabolism; Mice; Mice, Inbred C57BL; Interleukin-1beta/metabolism; Pyroptosis
Research Division(s): Inflammation
PubMed ID: 38514849
Publisher's Version: https://doi.org/10.1038/s41418-024-01281-x
Open Access at Publisher's Site: https://doi.org/10.1038/s41418-024-01281-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-03-27 08:35:46

Last Modified: 2024-06-28 03:08:38