Stress and the nonsense-mediated RNA decay pathway

Alexandra E. Goetz, Miles Wilkinson

Cells respond to internal and external cellular stressors by activating stress-response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway-nonsense-mediated RNA decay (NMD)-serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting that it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that "NMD therapy" may provide clinical benefit by downmodulating stress responses.