ИСТИНА

Short upstream open reading frames (uORFs) are found in 5’ untranslated regions of almost half of the human mRNAs. In many cases they significantly affect translation of the main coding regions and operate as regulatory elements under conditions of cell stress. A few molecular mechanisms have been proposed to explain their functions, including delayed reinitiation (exemplified by the yeast GCN4 or mammalian ATF4 mRNAs) and scanning ribosome obstruction (in the case of the mouse DDIT3 mRNA). The two mechanisms provide a translation preference of the particular mRNAs under conditions when translation initiation factor eIF2 is partially inactivated by phosphorylation. Here we describe a distinct uORF-dependent regulatory mechanism that operates on at least two human mRNAs, coding for translation factor eIF2D and ubiquitin ligase MDM2. The regulatory elements specifically reduce translation of the main reading frames during a mild hyperosmotic stress. This novel mechanism is based on a modulation of reinitiation rate but does not provide translation resistance to eIF2 phosphorylation. In vitro translation experiments showed that the reduction of reinitiation frequency are caused not by elevated salt concentration per se and suggest the presence of a hyperosmosis-induced signaling that leads to the uORF-dependent translation deregulation of specific mRNAs in mammalian cells.