Chronicles of a death foretold Dual sequential cell death checkpoints in TNF signaling

The kinase RIP1 wears a coat of many colors during TNF receptor signaling and can regulate both activation of prosurvival NF kappa B and programmed cell death pathways. In this review, we outline how coating RIP1 with K63-linked ubiquitin chains forms a protective layer that prevents RIP1 from binding apoptotic regulators and serves as an early guard against cell death. Further on, binding of NF kappa B signaling components to the ubiquitin coat of RIP1 activates long-term pro-survival signaling and forms a more impenetrable suit of armor against cell death. If RIP1 is not decorated with ubiquitin chains it becomes an unstoppable harbinger of bad news: programmed cell death.