| Autor: |
Newton, Kim, Wickliffe, Katherine E., Maltzman, Allie, Dugger, Debra L., Webster, Joshua D., Guo, Hongyan, Dixit, Vishva M. |
| Zdroj: |
Cell Death and Differentiation; 20240101, Issue: Preprints p1-9, 9p |
| Abstrakt: |
The proteolytic activity of caspase-8 suppresses lethal RIPK1-, RIPK3- and MLKL-dependent necroptosis during mouse embryogenesis. Caspase-8 is reported to cleave RIPK3 in addition to the RIPK3-interacting kinase RIPK1, but whether cleavage of RIPK3 is crucial for necroptosis suppression is unclear. Here we show that caspase-8-driven cleavage of endogenous mouse RIPK3 after Asp333is dependent on downstream caspase-3. Consistent with RIPK3 cleavage being a consequence of apoptosis rather than a critical brake on necroptosis, Ripk3D333A/D333Aknock-in mice lacking the Asp333cleavage site are viable and develop normally. Moreover, in contrast to mice lacking caspase-8 in their intestinal epithelial cells, Ripk3D333A/D333Amice do not exhibit increased sensitivity to high dose tumor necrosis factor (TNF). Ripk3D333A/D333Amacrophages died at the same rate as wild-type (WT) macrophages in response to TNF plus cycloheximide, TNF plus emricasan, or infection with murine cytomegalovirus (MCMV) lacking M36 and M45 to inhibit caspase-8 and RIPK3 activation, respectively. We conclude that caspase cleavage of RIPK3 is dispensable for mouse development, and that cleavage of caspase-8 substrates, including RIPK1, is sufficient to prevent necroptosis. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
Full text from SpringerLink