title: An outline of necrosome triggers.
abstract: Necroptosis was initially identified as a backup cell death program when apoptosis is blocked. However, it is now recognized as a cellular defense mechanism against infections and is presumed to be a detrimental factor in several pathologies driven by cell death. Necroptosis is a prototypic form of regulated necrosis that depends on activation of the necrosome, which is a protein complex in which receptor interacting protein kinase (RIPK) 3 is activated. The RIP homotypic interaction motif (RHIM) is the core domain that regulates activation of the necrosome. To date, three RHIM-containing proteins have been reported to activate the kinase activity of RIPK3 within the necrosome: RIPK1, Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), and DNA-dependent activator of interferon regulatory factors (DAI). Here, we review and discuss commonalities and differences of the increasing number of activators of the necrosome. Since the discovery that activation of mixed lineage kinase domain-like (MLKL) by RIPK3 kinase activity is crucial in necroptosis, interest has increased in monitoring and therapeutically targeting their activation. The availability of new phospho-specific antibodies, pharmacologic inhibitors, and transgenic models will allow us to further document the role of necroptosis in degenerative, inflammatory and infectious diseases.
authors.affiliation: Inflammation Research Center, VIB, 9000, Ghent, Belgium. Tom.VandenBerghe@irc.vib-ugent.be.|Department of Biomedical Molecular Biology, Ghent University, 9000, Ghent, Belgium. Tom.VandenBerghe@irc.vib-ugent.be.
authors.forename: Tom
authors.initials: T
authors.lastname: Vanden Berghe
authors.affiliation: Inflammation Research Center, VIB, 9000, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, 9000, Ghent, Belgium.|Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Physiology, Ghent University, 9000, Ghent, Belgium.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Hassannia
authors.affiliation: Inflammation Research Center, VIB, 9000, Ghent, Belgium. Peter.Vandenabeele@irc.vib-ugent.be.|Department of Biomedical Molecular Biology, Ghent University, 9000, Ghent, Belgium. Peter.Vandenabeele@irc.vib-ugent.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C476286:Ticam1 protein, mouse; C570694:MLKL protein, mouse; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse
keywords: MLKL; Necroptosis; Pathogens; RHIM; RIPK1; RIPK3