A beneficial adaptive role for CHOP in driving cell fate selection during ER stress

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 combine a new, versatile, genetically modified Chop allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we find that CHOP promotes death in some cells, but proliferation--and hence recovery--in others. Strikingly, this function of CHOP confers to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggest 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.

细胞应激可触发信号级联反应，这类反应既能够缓解引发的功能障碍，也可能启动细胞死亡程序。在内质网（endoplasmic reticulum, ER）应激过程中，转录因子CHOP被广泛认为可促进细胞死亡。然而，目前尚不清楚CHOP在细胞适应过程中是否也发挥有益作用。本研究结合一种新型多功能基因修饰Chop等位基因与单细胞分析技术，并采用生理强度的应激刺激，严谨探究了CHOP对细胞命运的调控作用。令人意外的是，我们发现CHOP在部分细胞中促进死亡，而在另一部分细胞中则促进增殖，进而推动细胞恢复。值得注意的是，CHOP的这一功能可赋予细胞对应特定应激的竞争性生长优势。单细胞层面的CHOP表达动力学与未折叠蛋白反应（unfolded protein response, UPR）激活情况表明，CHOP可最大化UPR的激活程度，进而有利于应激的缓解、后续UPR的失活以及细胞增殖。综上，本研究结果表明，CHOP的功能更适合被描述为一种"应激检测机制"，在生理强度的应激过程中，它可驱使细胞走向两种互斥的命运——适应或死亡。