Stress and the nonsense-mediated RNA decay pathway

Abstract

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 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.

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

“…A broad bioinformatic analysis on the RNASeq data from human cell lines with knockdowns of key NMD components UPF1, SMG6 or SMG7 demonstrated that the endoneucleolytic (SMG6-mediated) and exonucleolytic (SMG 5/7 mediated) decay routes are redundant, degrading mRNAs with introns in 3 UTR regions [43]. It has been observed that NMD targets with 5 upstream open reading frames (uORFs) and long 3 UTRs tend to be categorized as transcription factors, stress response genes and oncogenes [31,68].…”

AKT but not MYC promotes reactive oxygen species-mediated cell death in oxidative culture

“…4). In general, oxidative stress suppresses NMD in order to enhance the ability of cells to survive ROS toxicity (26,27).…”

“…S5B). To better understand how these pathways were regulated by galactose culture, we examined members of Nonsense-mediated mRNA decay (NMD) enhanced by the Exon Junction Complex (EJC), a surveillance pathway that eliminates mRNAs containing premature translation stop codons (26). Visualization of these proteins on a heatmap revealed that their basal expression was low in mAKT-expressing cells cultured in glucose and that short-term galactose induced higher expression ( Fig.…”

RNA Decay Factor UPF1 Promotes Protein Decay: A Hidden Talent

“…One possibility is that it is part of a feedback network to control muscle mass. Various stressors are known to inhibit NMD, probably as a means to regulate biological responses [26]. If exercise stress also inhibits NMD, this would be predicted to amplify myogenesis as a means to build muscle mass.…”

“…One line of evidence for this is the finding that mutations in the yeast UPF1 RING domain disrupt NMD [23]. Another line of evidence is studies demonstrating UPF1-dependent decay of peptides translated from PTC-containing transcripts [26][27]. In the future, it will be intriguing to determine whether the mechanism responsible for this UPF1 dependent peptide decay in yeast is UPF1’s E3 ligase activity.…”