Blandine C. Mercier1,5, Emmanuel Labaronne2,3,5, David Cluet2,5, Laura Guiguettaz2, Nicolas Fontrodona2, Alicia Bicknell1,6, Antoine Corbin4, Mélanie Wencker4, Fabien Aube2, Laurent Modolo2, Karina Jouravleva2, Didier Auboeuf2, Melissa J. Moore1,6 and Emiliano P. Ricci2 1RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA; 2Laboratory of Biology and Modeling of the Cell (LBMC), Université de Lyon, ENS de Lyon, Université Claude Bernard, CNRS UMR 5239, Inserm U1293, 69007 Lyon, France; 3ADLIN Science, 9100 Evry-Courcouronnes, France; 4Centre International de Recherche en Infectiologie Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007 Lyon, France

↵5 These authors contributed equally to this work.

↵6 Present address: Moderna, Inc., Cambridge, MA 02139, USA

Corresponding authors: emiliano.ricciens-lyon.org, melissa.mooreumassmed.edu Abstract

mRNA translation and decay are tightly interconnected processes both in the context of mRNA quality-control pathways and for the degradation of functional mRNAs. Cotranslational mRNA degradation through codon usage, ribosome collisions, and the recruitment of specific proteins to ribosomes is an important determinant of mRNA turnover. However, the extent to which translation-dependent mRNA decay (TDD) and translation-independent mRNA decay (TID) pathways participate in the degradation of mRNAs has not been studied yet. Here we describe a comprehensive analysis of basal and signal-induced TDD and TID in mouse primary CD4+ T cells. Our results indicate that most cellular transcripts are decayed to some extent in a translation-dependent manner. Our analysis further identifies the length of untranslated regions, the density of ribosomes, and GC3 content as important determinants of TDD magnitude. Consistently, all transcripts that undergo changes in ribosome density within their coding sequence upon T cell activation display a corresponding change in their TDD level. Moreover, we reveal a dynamic modulation in the relationship between GC3 content and TDD upon T cell activation, with a reversal in the impact of GC3- and AU3-rich codons. Altogether, our data show a strong and dynamic interconnection between mRNA translation and decay in mammalian primary cells.

Footnotes

[Supplemental material is available for this article.]

Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.277863.123.

Freely available online through the Genome Research Open Access option.

Received March 7, 2023. Accepted March 9, 2024.