| First Author | Petersen SL | Year | 2015 |
| Journal | Cell Death Differ | Volume | 22 |
| Issue | 11 | Pages | 1846-57 |
| PubMed ID | 25882049 | Mgi Jnum | J:258948 |
| Mgi Id | MGI:6140258 | Doi | 10.1038/cdd.2015.35 |
| Citation | Petersen SL, et al. (2015) TRAF2 is a biologically important necroptosis suppressor. Cell Death Differ 22(11):1846-57 |
| abstractText | Tumor necrosis factor alpha (TNFalpha) triggers necroptotic cell death through an intracellular signaling complex containing receptor-interacting protein kinase (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)-driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)-previously implicated in apoptosis suppression-also inhibits necroptotic signaling by TNFalpha. TRAF2 disruption in mouse fibroblasts augmented TNFalpha-driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFalpha reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon alpha receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo. |
