Programmed necrosis, also known as necroptosis

Read Also

In 1998, inhibition of caspase activity was shown to sensitize the fibroblastic L929 cell line to TNF-mediated necrotic cell death [39]. With respect to the CD95 signal, Tschopp et al. showed that FADD and RIP1 participate in the implementation of a non-apoptotic signaling pathway that leads to a necrotic morphology associated with loss of plasma membrane integrity but not with chromatin condensation [38]. Of note, BID cleavage was not observed in the context of this necrotic signal. Whereas FADD plays a crucial role in both apoptotic and necrotic pathways, RIP1 recruitment to CD95 occurs independently of this adaptor protein. Indeed, yeast two-hybrid experiments showed that RIP1 can bind directly to the CD95 DD, whereas this interaction is lost when a bait corresponding to mutated CD95-DD (replacement of Val 238 to Asn) is used [143]. In addition, RIP3 (RIPK3, a member of the RIP kinase family) is an indispensable factor for the induction of the necrotic signaling pathway [70-72]. Identification of necrostatin, a chemical inhibitor of necroptosis [144] that specifically inhibits RIP1 kinase activity [145], has accelerated the pace of discovery in this field of cell death. The apoptosis and necroptosis pathways interact: for instance, caspase-8 exerts a potent inhibitory effect on CD95 and TNFR1-mediated necroptosis [146] through its ability to process and inactivate RIP1 and RIP3 [147, 148]. At least in the case of TNF signaling, the necrotic signal relies on the activity of CYLD, a deubiquitinating enzyme that is also cleaved and inactivated by caspase-8 [149].

Overall, these findings suggest that the apoptotic machinery controls the necrotic pathway. This concept was recently confirmed by the results of in vivo double-KO experiments [41-43, 150]. Indeed, FADD and caspase-8 can be considered to be a pro-survival factor, mainly because both of these two “apoptotic” molecules inhibit the RIP1/RIP3-dependent necrotic signal; consequently, their loss unleashes the necroptotic program and leads to embryonic lethality. However, most studies on necroptosis have focused on the TNF signaling pathway, whereas the mechanism by which CD95 elicits this cell death pathway, as well as how this receptor switches between non-apoptotic, apoptotic, and necroptotic signals, remains to be elucidated. Importantly, the impact of each type of cell death on antigen presentation, and on the efficiency of immune response after elimination of infected or transformed cells, also remains unclear