Environmental stresses suppress nonsense-mediated mRNA decay (NMD) and affect cells by stabilizing NMD-targeted gene expression

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.

Tau‐induced deficits in nonsense‐mediated mRNA decay contribute to neurodegeneration

“…14 Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved, translation-dependent RNA surveillance mechanism that recognizes and degrades PTC-and other error-containing transcripts as well as many naturally occurring, error-free transcripts. The ability of NMD to also target "normal" mRNA transcripts is important for a wide range of physiological pathways including differentiation and proliferation, 15,16 development, [17][18][19][20] viral defense, 21,22 stress response, [23][24][25] and neuronal activity (eg, synaptic plasticity and axonal guidance). [26][27][28] NMD machinery consists of several core factors that were first discovered in yeast as the up-frameshift-1 (Upf1), Upf2, and Upf3 genes.…”

Identification and Validation of UPF1 as a Novel Prognostic Biomarker in Renal Clear Cell Carcinoma

“…We propose that there might be two main reasons for the inconsistent expression trend of UPF1 in different cancers. Firstly, it was reported that oxidative stress and endoplasmic reticulum (ER) stress could suppress NMD through the phospho-eIF2α/ATF4 pathway [ 54 ]. This might explain the low expression of UPF1 in renal cancer, which has feature enhanced oxidative stress.…”

Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons

“…One possibility is that defective spliceosome formation causes abnormal mRNAs, which subsequently promote nonsense-mediated mRNA decay (NMD). Considering that PERK expression is involved in NMD suppression,[ 55 , 56 ] the over-activated NMD possibly induces downregulation of PERK. The underlying mechanism between DGCR14 and PERK will be the next primary question for a future study.…”