Gardner Lawrence B
New York University School of Medicine, Department of Medicine, Division of Hematology, New York City, New York 10016, USA.
Mol Cell Biol. 2008 Jun;28(11):3729-41. doi: 10.1128/MCB.02284-07. Epub 2008 Mar 24.
Nonsense-mediated RNA decay (NMD) rapidly degrades both mutated mRNAs and nonmutated cellular mRNAs in what is thought to be a constitutive fashion. Here we demonstrate that NMD is inhibited in hypoxic cells and that this inhibition is dependent on phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). eIF2alpha phosphorylation is known to promote translational and transcriptional up-regulation of genes important for the cellular response to stress. We show that the mRNAs of several of these stress-induced genes are NMD targets and that the repression of NMD stabilizes these mRNAs, thus demonstrating that the inhibition of NMD augments the cellular stress response. Furthermore, hypoxia-induced formation of cytoplasmic stress granules is also dependent on eIF2alpha phosphorylation, and components of the NMD pathway are relocalized to these granules in hypoxic cells, providing a potential mechanism for the hypoxic inhibition of NMD. Our demonstration that NMD is inhibited in hypoxic cells reveals that the regulation of NMD can dynamically alter gene expression and also establishes a novel mechanism for hypoxic gene regulation.
无义介导的RNA降解（NMD）以一种被认为是组成型的方式快速降解突变的mRNA和未突变的细胞mRNA。在此我们证明，NMD在缺氧细胞中受到抑制，且这种抑制依赖于真核起始因子2（eIF2α）α亚基的磷酸化。已知eIF2α磷酸化可促进对细胞应激反应重要的基因的翻译和转录上调。我们表明，其中几个应激诱导基因的mRNA是NMD的靶标，并且NMD的抑制使这些mRNA稳定，从而证明NMD的抑制增强了细胞应激反应。此外，缺氧诱导的细胞质应激颗粒的形成也依赖于eIF2α磷酸化，并且NMD途径的组分在缺氧细胞中重新定位到这些颗粒，为缺氧对NMD的抑制提供了一种潜在机制。我们关于NMD在缺氧细胞中受到抑制的证明揭示了NMD的调控可以动态改变基因表达，并且还建立了一种新的缺氧基因调控机制。
