Control of life-or-death decisions by RIP1 kinase

RIP1 kinase, a multifunctional protein that contains an N-terminal Ser/Thr kinase and a C-terminal death domain, has emerged as a key regulatory molecule involved in regulating both cell death and cell survival. When the proinflammatory cytokine TNFα stimulates its receptor, TNFR1, RIP1 regulates whether the cell lives by activating NF-κB or dies by apoptosis or necroptosis, two distinct pathways of programmed cell death that may be activated to eliminate unwanted cells. The kinase domain of RIP1 is involved in regulating necroptosis, and the death domain regulates RIP1 recruitment to the intracellular domain of TNFR1. The intermediate domain of RIP1 activates NF-κB and also interacts with RIP3 kinase, a downstream mediator of RIP1 in the execution of necroptosis. This review focuses on the functional roles of RIP1 in regulating multiple cellular mechanisms, the dynamic regulation of RIP1, and the physiological and pathological roles of RIP1 kinase in human health and disease.