NFκB and ubiquitination: Partners in disarming RIPK1-mediated cell death

The mechanisms regulating cell survival and thus its corollary, cell death, have been intensively studied over the last two decades. Recent studies have shed new light into how non-degradative ubiquitination of the kinase RIPK1 is critical in determining this cell fate. In this review, we summarize recent findings on how ubiquitination of RIPK1 constitutes a survival signal through both NFκB-independent and NFκB-dependent mechanisms. However, in the absence of ubiquitination, RIPK1 becomes a death-signaling molecule capable of engaging both the caspase-dependent apoptosis machinery and the recently described RIPK3-dependent necroptosis machinery. Another layer of complexity is now emerging in that components of the ubiquitin-modifying machinery are themselves regulated by proteolytic processing. This survival/death regulatory mechanism has been best analyzed in the context of TNF receptor signaling, but it is likely that principles learned from TNFR may be applicable to other immune receptors including the antigen and Toll-like receptors.