Liu Kaihua, Zhao Chaoxian, Adajar Reed C, DeZwaan-McCabe Diane, Rutkowski D Thomas
Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA.
Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
bioRxiv. 2023 Oct 23:2023.03.19.533325. doi: 10.1101/2023.03.19.533325.
Cellular stresses elicit signaling cascades that are capable of either mitigating the inciting dysfunction or initiating cell death. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. However, it is not clear whether CHOP also has a beneficial role during adaptation. Here, we have combined a new, versatile, genetically modified allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we found that CHOP promoted death in some cells, but proliferation-and hence recovery-in others. Strikingly, this function of CHOP conferred to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggested that CHOP maximizes UPR activation, which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. 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-adaptation or death-during stresses of physiological intensity.
细胞应激会引发信号级联反应，这些反应能够减轻引发的功能障碍或启动细胞死亡。在内质网（ER）应激期间，转录因子CHOP被广泛认为会促进细胞死亡。然而，尚不清楚CHOP在适应性过程中是否也具有有益作用。在这里，我们将一种新的、通用的、经过基因改造的等位基因与单细胞分析以及生理强度的应激相结合，以严格检验CHOP对细胞命运的贡献。矛盾的是，我们发现CHOP在一些细胞中促进死亡，但在另一些细胞中促进增殖——从而促进恢复。引人注目的是，CHOP的这种功能赋予细胞一种应激特异性的竞争性生长优势。单细胞水平上CHOP表达和未折叠蛋白反应（UPR）激活的动态变化表明，CHOP能使UPR激活最大化，进而有利于应激解决、随后的UPR失活和增殖。综上所述，这些发现表明，CHOP的功能可以更好地描述为一种“应激测试”，在生理强度的应激期间，它会驱使细胞进入两种相互排斥的命运之一——适应或死亡。
