The serine-threonine kinase RIPK1 regulates not only cell survival mediated by induction of the transcription factor NF-κB but also cell death by inducing apoptosis or necroptosis. In Nature, Takahashi et al. show that RIPK1 suppresses caspase 8-dependent apoptosis but not RIPK3-dependent necroptosis in intestinal epithelial cells. Mice with conditional deletion of RIPK1 in the gut epithelium undergo massive and lethal death of intestinal epithelial cells and intestinal inflammation dependent on bacterial colonization and signaling through TLRs and the receptor TNFR1. Deletion of caspase-8 completely 'rescues' the apoptosis of intestinal epithelial cells in RIPK1-deficient mice, but deletion of TNFR1 does not. Moreover, TNF-induced activation of NF-κB is intact in RIPK1-deficient cells. Thus, RIPK1 deficiency sensitizes the intestinal epithelium to TNF-induced, caspase 8-mediated apoptosis independently of defects in NF-κB activation, which suggests a prosurvival role for RIPK1 in these cells.

Nature 513, 95–99 (2014)