More to life than death: molecular determinants of necroptotic and non-necroptotic RIP3 kinase signaling

Necroptosis describes a pro-inflammatory form of cell death governed by the kinases RIP1 and RIP3. Necroptosis can occur following stimulation of the DNA receptor, DAI, or activation of death receptor, Toll-like receptor, T-cell antigen receptor, or interferon receptor signaling. Analysis of RIP3 deficient mice has implicated necroptosis in several inflammatory-driven diseases, including atherosclerosis, alcoholic liver disease and retinal degeneration. Although studies have demonstrated that mixed lineage kinase domain-like (MLKL) is the only substrate of RIP3 kinase that is essential for necroptotic death, the molecular determinants acting downstream of MLKL remain ambiguous. In addition, RIP3 can signal necroptosis independent of RIP1, may induce apoptosis, and can directly promote pro-inflammatory cytokine production. Therefore it will be important to determine if non-necroptotic RIP3 signaling influences RIP3 dependent pathologies.