Abstract
Nonsense-mediated mRNA decay (NMD) is a cellular mechanism that eliminates mRNAs that harbor premature translation termination codons (PTCs). Here, we investigated the effects of environmental stresses (oxidative stress and endoplasmic reticulum (ER) stress) on NMD activity. Methylmercury (MeHg) was used to cause oxidative stress and thapsigargin to stress the ER. NMD suppression, evidenced by upregulation of NMD-sensitive mRNAs and a decrease in UPF1 phosphorylation, was observed in MeHg-treated myogenic cells, cerebral cortical neuronal cells, and astroglial cells. Mild ER stress amplified NMD suppression caused by MeHg. To elucidate the cause of stress-induced NMD suppression, the role of the phospho-eIF2α/ATF4 pathway was investigated. Knockdown and non-phosphorylatable eIF2α-transfection studies demonstrated the critical role of phospho-eIF2α-mediated repression of translation in mild ER stress-induced NMD suppression. However, NMD suppression was also observed in phospho-eIF2α-deficient cells under mild ER stress. Mechanistic target of rapamycin suppression-induced inhibition of cap-dependent translation, and downregulation of the NMD components UPF1, SMG7, and eIF4A3, were probably involved in stress-induced NMD suppression. Our results indicate that stress-induced NMD suppression has the potential to affect the condition of cells and phenotypes of PTC-related diseases under environmental stresses by stabilizing NMD-targeted gene expression.
Highlights
It has been demonstrated that several stress-induced genes possessing uORFs, or other features prone to premature translation termination codons (PTCs), such as alternatively spliced transcripts, are targeted by Nonsense-mediated mRNA decay (NMD), the inhibition of which stabilizes their cognate mRNAs and augments the cellular stress responses[14,15,16]
Suppression of NMD was evidenced by upregulation of NMD target non-protein-coding small nucleolar RNA host gene 1 (Snhg1) or growth arrest-specific 5 (Gas5) mRNA harboring PTCs
We have demonstrated the effects of depleting NMD effectors (SMG1 and SMG7) on the upregulation of Snhg[1] mRNAs during endoplasmic reticulum (ER) stress[29]
Summary
It has been demonstrated that several stress-induced genes possessing uORFs, or other features prone to PTCs, such as alternatively spliced transcripts, are targeted by NMD, the inhibition of which stabilizes their cognate mRNAs and augments the cellular stress responses[14,15,16]. We hypothesized that environmental stresses suppressing NMD might thereby affect the expression of truncated proteins that arise from PTCs. Here, we aimed to investigate the effects of two environmental stresses, oxidative stress and mild ER stress, on NMD activity in the mouse MeHg-susceptible myogenic cell line C2C12-DMPK16018,19 and rat central nervous system cells [cerebral cortical neuronal cells (CNCs) and astroglial cells (AGCs)]. Our results demonstrated that environmental stresses induce NMD suppression in aforementioned cells, suggesting that this may be a mechanism through which these stresses affect cellular condition. We further investigated the mechanism of NMD suppression induced by mild ER stress using mutant cells expressing non-phosphorylatable eIF2α. We demonstrated that phospho-eIF2α-mediated repression of translation plays a critical role, and that mechanistic target of rapamycin (mTOR) suppression-induced inhibition of cap-dependent translation, and downregulation of the NMD components UPF1, SMG7, and eIF4A3 are involved in environmental stress-induced NMD suppression
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