TRANSLATIONAL ATTENUATION MEDIATED BY AN MESSENGER-RNA INTRON

Background: The unfolded protein response (UPR) is an intracellular si gnaling pathway that is activated by the accumulation of unfolded prot eins in the endoplasmic reticulum (ER). The UPR results in an increase in transcription of ER-resident proteins that facilitate protein fold ing in the ER. A key regulatory step in UPR activation is the regulate d splicing of HAC1 mRNA, which encodes Hac1p, a transcription factor d edicated to this pathway. Hac1p can be detected only when the spliced form of HAC1 mRNA (termed HAC1(i) mRNA, for induced) is produced; this was surprising because the unspliced HAC1(u) mRNA (HAC1(u) for unindu ced) is equally stable in cells. Results: We show that in contrast to most other unspliced pre-mRNAs, the HAC1(u) mRNA is transported from t he nucleus into the cytosol. Although HAC1(u) mRNA is associated with polyribosomes, no delectable Hac1p(u) is produced unless the intron is removed, indicating that the presence of the intron prevents mRNA tra nslation. When it is produced, Hac1p(u) has a stability similar to tha t of Hac1p(i), the form of the Hac1p that is produced from the spliced mRNA and that differs from Hac1p(u) by a short carboxy-terminal tail sequence. Hac1p(u), however, is differently modified and less active i n activating transcription. Interestingly, when transplanted into the 3' untranslated region of a completely unrelated mRNA, the HAC1 intron is sufficient to attenuate translation of the preceding open reading frame. Conclusions: We have shown that the HAC1 mRNA intron is both ne cessary and sufficient to prevent complete translation of polyribosome -associated mRNAs. To our knowledge, this identifies a new way by whic h translation of a mRNA can be attenuated.