TNF can activate RIPK3 and cause programmed necrosis in the absence of RIPK1
- Author(s)
- Moujalled, DM; Cook, WD; Okamoto, T; Murphy, J; Lawlor, KE; Vince, JE; Vaux, DL;
- Journal Title
- CELL DEATH & DISEASE
- Publication Type
- Journal Article
- Abstract
- Ligation of tumor necrosis factor receptor 1 (TNFR1) can cause cell death by caspase 8 or receptor-interacting protein kinase 1 (RIPK1)- and RIPK3-dependent mechanisms. It has been assumed that because RIPK1 bears a death domain (DD), but RIPK3 does not, RIPK1 is necessary for recruitment of RIPK3 into signaling and death-inducing complexes. To test this assumption, we expressed elevated levels of RIPK3 in murine embryonic fibroblasts (MEFs) from wild-type (WT) and gene-deleted mice, and exposed them to TNF. Neither treatment with TNF nor overexpression of RIPK3 alone caused MEFs to die, but when levels of RIPK3 were increased, addition of TNF killed WT, Ripk1(-/-), caspase 8(-/-), and Bax(-/-)/Bak(-/-) MEFs, even in the presence of the broad-spectrum caspase inhibitor Q-VD-OPh. In contrast, Tnfr1(-/-) and Tradd(-/-) MEFs did not die. These results show for the first time that in the absence of RIPK1, TNF can activate RIPK3 to induce cell death both by a caspase 8-dependent mechanism and by a separate Bax/Bak- and caspase-independent mechanism. RIPK1 is therefore not essential for TNF to activate RIPK3 to induce necroptosis nor for the formation of a functional ripoptosome/necrosome. Cell Death and Disease (2013) 4, 465; doi:10.1038/cddis.2012.201; published online 17 January 2013
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- INDUCED CELL-DEATH; NF-KAPPA-B; MIXED LINEAGE KINASE; INDUCED APOPTOSIS; FACTOR RECEPTOR; DOMAIN-LIKE; ALPHA; COMPLEX; INHIBITOR; TARGET
- Research Division(s)
- Cell Signalling And Cell Death; Structural Biology; Inflammation
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563989/
- Publisher's Version
- https://doi.org/10.1038/cddis.2012.201
- Open Access at Publisher's Site
http://www.nature.com/cddis/journal/v4/n1/full/cddis2012201a.html- Terms of Use/Rights Notice
- This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.
Creation Date: 2013-01-01 12:00:00