TRIF:activated TLR3/TLR4 RIP3:TRIF:activated TLR3/TLR4 RIP3 binds TRIF to mediate necroptosis Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 GENE ONTOLOGYGO:0060555 Pubmed12181749 Pubmed15814722 Pubmed21737330 Pubmed22123964 Reactome Database ID Release 432569057 Reactome, http://www.reactome.org ReactomeREACT_150365 Reviewed: Fitzgerald, Katherine A, 2012-11-13 TLR3 and TLR4 -directed programmed necrosis (necroptosis) is mediated by the TRIF-RIP3 pathway in mouse macrophages [He S e al 2011]. RIP3 was shown to be essential mediator in TLR3-induced necroptotic cell death in human epithelial cell lines. Knockdown of RIP3 in human keratinocyte HaCaT cells blocked TLR3-mediated necroptosis without affecting the apoptotic response. Moreover, overexpression of RIP3 in human epithelial carcinoma cell line HeLa led to increased caspase-independent TLR3-induced cell death in the absence of IAPs [Feoktistova M et al 2011]. In addition, in caspase-8- or FADD-deficient human Jurkat cells dsRNA induced programmed necrosis, instead of apoptosis [Kalai M et al 2002]. Thus, when caspase-dependent apoptosis is inhibited or absent, the alternative RIP3-mediated programmed cell death is induced. has a Stoichiometric coefficient of 4