The origin and evolution of necroptosis signaling pathway in metazoa.

Necroptosis, a new form of cell death, is attracting significant attention as it is involved in the development and progression of many diseases in mammals. The structural domains and evolutionary principles of necroptotic components as well as the potential activation mechanism are not well understood in lower vertebrates and invertebrates. In the present study, TNFα, TNFR1, TLR3 and TLR4 are all presented in Mollusca and even higher phyla. ZBP1, TRADD and TRIF are only in some vertebrates. RIPK1/3 and MLKL are early originated from Mollusca and Echinodermata, respectively. Among which, RIPK1 with RHIM and Death domain and RIPK3 with a STYKc domain and two cRHIMs in Mollusca may fuse to be the classical RIPK1/3. More importantly, RIPK1/3 in Mollusca also provides structural domain conditions for the generation of the later ZBP1/TRADD/TRIF and MLKL, respectively. Taken together, necroptotic components in Mollusca are important fundamental for the evolution of necroptotic pathways. These findings provide insights into the evolutionary principles of necroptotic components and the possible activation mechanism of necroptosis pathways in various species.