Trying to protect animals from one form of cell death may lead to death by another. Two protein kinases, known as RIPK1 and RIPK3, promote signaling that leads to cell death by necroptosis. However, Newton et al. (see the Perspective by Zhang and Chan) found that inhibition of RIPK3 was not always beneficial. Instead, mice expressing a form of RIPK3 with no catalytic activity died from increased apoptotic cell death, but animals lacking the RIPK3 protein entirely did not die, perhaps because RIPK3 restrains apoptosis mediated by caspase-8 by an independent mechanism.
K. Newton, D. L. Dugger, K. E. Wickliffe, N. Kapoor, M. C. de Almagro, D. Vucic, L. Komuves, R. E. Ferrando, D. M. French, J. Webster, M. Roose-Girma, S. Warming, V. M. Dixit, Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014). [Abstract] [Full Text]