Figure 5.

NMD activity is regulated during stress response. Under normal conditions (green) NMD destabilizes IRE1α mRNA, a central UPR component, thereby preventing UPR activation. Under ER stress (red) UPR is activated and inhibits NMD via eIF2α phosphorylation, triggering IRE1α accumulation and hence a robust UPR activation. Stress‐induced inhibition of NMD also results in a higher accumulation of ATF4, a transcriptional activator of the integrated stress response (ISR) with uORFs in its mRNA. Therefore, modulation of NMD activity plays a key role in the initial phase of the stress response. In conditions of prolonged stress, the UPR and ISR pathways activate a proapoptotic program. In cells undergoing apoptosis, NMD activity can be further downregulated by the production of caspase‐derived proteolytic forms of UPF1. This establishes a reinforcing feedback loop that will irreversibly commit the cell to apoptosis.