CHOP drives cells to mutually exclusive cell fates--death and proliferation--during ER stress

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.19.533325v1?rss=1 Authors: Liu, K., Zhao, C., Rutkowski, D. T. Abstract: Cellular stresses elicit signaling cascades that are capable of both mitigating the inciting dysfunction and initiating cell death when the stress cannot be overcome. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. Yet CHOP carries out this function largely by augmenting protein synthesis, which is an essential component of recovery from stress. It is thus not clear whether CHOP also has a beneficial role during that recovery. Here, we have created a new, versatile, genetically modified Chop allele to rigorously examine the contribution of CHOP to cell fate. Surprisingly, we found that, while CHOP favored death in some cells, it also stimulated proliferation, and hence recovery, in others. This outcome arose at least in part from the same promotion of protein synthesis that is known to lead to cell death. Strikingly, this function of CHOP conferred a competitive growth advantage on cells that were exposed to conditions of ER stress that permitted adaptation. Single cell RNA sequencing revealed that CHOP-mediated proliferation was associated with attenuated UPR activation, while also unveiling a surprising and previously unappreciated heterogeneity in the cellular response to ER stress. Taken together, these findings suggest that CHOP's function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates--recovery or death--during stress. They point to a previously unappreciated pro-survival function of CHOP during stresses of physiological intensity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC