2. Academic Validation
  3. RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation

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

  • Cell Death Differ. 2024 Mar 21. doi: 10.1038/s41418-024-01281-x.
Hong Tri Tran 1 2,  Tobias Kratina 1,  Auriane Coutansais 1,  Dominika Michalek 1 2,  Benjamin M Hogan 1 2 3,  Kate E Lawlor 4 5,  James E Vince 6 7,  John Silke 6 7,  Najoua Lalaoui 8 9 10
Affiliations

Affiliations

  • 1 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
  • 3 Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, Australia.
  • 4 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • 5 Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • 6 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 7 Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • 8 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. najoua.lalaoui@petermac.org.
  • 9 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. najoua.lalaoui@petermac.org.
  • 10 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. najoua.lalaoui@petermac.org.
PMID: 38514849 DOI: 10.1038/s41418-024-01281-x
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 RIPK3D333A/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, RIPK3D333A/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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z