Short upstream open reading frames (uORFs) are the most prevalent cis-acting regulatory elements in the mammalian transcriptome which can orchestrate mRNA translation. Apart from being “passive roadblocks” that decrease expression of the main coding regions, particular uORFs can serve as specific sensors for changing conditions, thus regulating translation in response to cell stress. Here we report a novel uORF-based regulatory mechanism that is employed under conditions of hyperosmotic stress by at least two human mRNAs, coding for translation reinitiation/recycling factor eIF2D and E3 ubiquitin ligase MDM2. This novel mode of translational control selectively downregulates their expression and requires as few as one uORF. Using a set of reporter mRNAs and fleeting mRNA transfection (FLERT) technique, we provide evidence that the phenomenon does not rely on delayed reinitiation, altered AUG recognition, ribosome stalling, mRNA destabilization or other known mechanisms. Instead, it is based on events taking place at uORF stop codon or immediately downstream. Functional aspects and implications of the novel regulatory mechanism to cell physiology are discussed.

短的上游开放阅读框（uORF）是最普遍的顺式转录组中可发挥作用的调节元件，可协调mRNA的翻译。除了是降低主要编码区域表达的“被动障碍”之外，特定的uORF可以用作改变条件的特定传感器，从而响应细胞应激来调节翻译。在这里，我们报告了一种基于uORF的新型调节机制，该机制在高渗应激条件下至少由两个人类mRNA编码，编码翻译重新初始化/循环因子eIF2D和E3泛素连接酶MDM2。这种新颖的翻译控制模式选择性地下调了它们的表达，并需要少至一个uORF。使用一套报告基因mRNA和短暂的mRNA转染（FLERT）技术，我们提供了证据，表明该现象不依赖于延迟的重新初始化，改变的AUG识别，核糖体失速，mRNA不稳定或其他已知机制。相反，它基于uORF终止密码子或紧接下游发生的事件。讨论了功能方面以及新型调节机制对细胞生理的影响。