Crucial roles of Grr1 in splicing and translation of HAC1 mRNA upon unfolded stress response

Nichika Sato, Yu Nakano, Yasuko Matsuki, Shota Tomomatsu, Sihan Li, Yoshitaka Matsuo and Toshifumi Inada ()
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Nichika Sato: The University of Tokyo
Yu Nakano: Tohoku University
Yasuko Matsuki: Tohoku University
Shota Tomomatsu: The University of Tokyo
Sihan Li: The University of Tokyo
Yoshitaka Matsuo: The University of Tokyo
Toshifumi Inada: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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, 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, an E3 ligase, Grr1, an F-box protein component of the SCF ubiquitin ligase complex, which is responsible for Ubp3 degradation, has been identified. Grr1-mediated Ubp3 degradation is required to maintain the level of eS7A monoubiquitination that facilitates Hac1p translation depending on the ORF of HAC1i. Grr1 also facilitates the splicing of HAC1u mRNA independently of Ubp3 and eS7A ubiquitination. Finally, we propose distinct roles of Grr1 upon UPR, HAC1u splicing, and HAC1i mRNA translation. Grr1-mediated Ubp3 degradation is crucial for HAC1i mRNA translation, highlighting the crucial role of ribosome ubiquitination in translational during UPR.

Date: 2025
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DOI: 10.1038/s41467-025-57360-1

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