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

Abstract

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.

Synopsis

The stress-regulated protein CHOP acts as a stress test on the ER, promoting cell proliferation and adaptation during ER stresses of mild intensity through the same pathway by which it promotes cell death during severe stress.

• CHOP stimulates cell proliferation through the promotion of protein synthesis.

• The exacerbation of ER stress by CHOP stimulates maximal UPR activation and drives cells into either adaptation or death.

• Cells expressing CHOP have a competitive advantage over CHOP-deleted cells during mild but chronic stress.

Abstract

The stress-regulated protein CHOP acts as a stress test on the ER, promoting cell proliferation and adaptation during ER stresses of mild intensity through the same pathway by which it promotes cell death during severe stress.