The Greatwall-Endosulfine-PP2A/B55 pathway regulates entry into quiescence by enhancing translation of Elongator-tunable transcripts

Encinar del Dedo, Javier; Suárez, M. Belén; López-San Segundo, Rafael; Vázquez Bolado, Alicia; Sun, Jingjing; García Blanco, Natalia; García, Patrícia; Tricquet, Pauline; Chen, Jun-Song; Dedon, Peter C.; Gould, Kathleen L.; Hidalgo Hernando, Elena; Hermand, Damien; Moreno, Sergio

doi:http://dx.doi.org/10.1038/s41467-024-55004-4

The Greatwall-Endosulfine-PP2A/B55 pathway regulates entry into quiescence by enhancing translation of Elongator-tunable transcripts

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Encinar Del Dedo J, Suárez MB, López-San Segundo R, Vázquez-Bolado A, Sun J, García-Blanco N, et al. The Greatwall-Endosulfine-PP2A/B55 pathway regulates entry into quiescence by enhancing translation of Elongator-tunable transcripts. Nat Commun. 2024 Dec 5;15(1):10603. DOI: 10.1038/s41467-024-55004-4

Abstract

Quiescent cells require a continuous supply of proteins to maintain protein homeostasis. In fission yeast, entry into quiescence is triggered by nitrogen stress, leading to the inactivation of TORC1 and the activation of TORC2. In this study, we demonstrate that the Greatwall-Endosulfine-PPA/B55 pathway connects the downregulation of TORC1 with the upregulation of TORC2, resulting in the activation of Elongator-dependent tRNA modifications crucial for sustaining the translation programme during entry into quiescence. This mechanism promotes U34 and A37 tRNA modifications at the anticodon stem loop, enhancing translation efficiency and fidelity of mRNAs enriched for AAA versus AAG lysine codons. Notably, several of these mRNAs encode TORC1 inhibitors, TORC2 activators, tRNA modifiers, and proteins necessary for telomeric and subtelomeric functions. Therefore, we propose a mechanism by which cells respond to nitrogen stress at the level of translation, involving a coordinated interplay between tRNA epitranscriptome and biased codon usage.