Grr1-mediated Ubp3 degradation is crucial for HAC1 mRNA translation and unfolded stress response in yeast

Abstract

In the process of the unfolded protein response (UPR), the Hac1p protein is induced through a complex regulation of the HAC1 mRNA. This includes the mRNA localization on the endoplasmic reticulum (ER) membrane and stress-triggered splicing. In yeast, a specific ribosome ubiquitination process, the monoubiquitination of eS7A by the E3 ligase Not4, facilitates the translation of HAC1ⁱ, which is a spliced form of the HAC1 mRNA. Upon UPR, the mono-ubiquitination of eS7A increases due to the downregulation of Ubp3, a deubiquitinating enzyme of eS7A. However, the exact mechanisms behind these regulations have remained unknown. In this study, a novel E3 ligase, Grr1, an F-box protein component of the SCF ubiquitin ligase complex, which is responsible for Ubp3 degradation, has been identified. Grr1 is crucial to maintain the level of eS7A monoubiquitination upon UPR and HAC1ⁱ mRNA translation. In addition to the crucial role of untranslated regions in HAC1ⁱ mRNA translation, eS7A monoubiquitination facilitates Hac1 expression depending on the ORF of HAC1ⁱ. In summary, the proposed model is that the Grr1-mediated degradation of Ubp3 upregulates eS7A monoubiquitination, leading to HAC1ⁱ translation. This study highlights the crucial role of ribosome ubiquitination in translational control during UPR.