More to Life than NF-κB in TNFR1 Signaling

TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders has long been attributed to induction of proinflammatory mediators. TNF also activates cell survival and death pathways, and recent studies demonstrated that TNF also causes inflammation by inducing cell death. The default response of most cells to TNF is survival and NF-κB-mediated upregulation of prosurvival molecules is a well-documented protective mechanism downstream of TNFR1. Recent studies revealed the existence of an NF-κB-independent cell death checkpoint that restricts cell demise by inactivating RIPK1. Disruption of this checkpoint leads to RIPK1 kinase-dependent death and causes inflammation in vivo. These revelations bring complexity to the control of TNF-induced cell death, and suggest clinical benefit of RIPK1 inhibitors in TNF-driven human inflammatory disorders.

TrendsTNF can cause inflammation by activating NF-κB transcriptional responses, as well as by inducing cell death, in the form of apoptosis and necroptosis.The NF-κB-mediated upregulation of prosurvival molecules serve as a late cell death checkpoint protecting cells from TNF-mediated RIPK1-independent apoptosis.A receptor proximal NF-κB-independent cell death checkpoint protects the cells from TNF-mediated RIPK1 kinase-dependent apoptosis and necroptosis.This early checkpoint inactivates RIPK1 via a two-step mechanism that promotes ubiquitylation of RIPK1 first and phosphorylation of RIPK1 second.Inactivating the kinase activity of RIPK1 prevents inflammation in TNF-driven murine models of inflammation; RIPK1 kinase inhibitors may thus have great clinical benefit in TNF-mediated human pathologies.