Glucocorticoids Modulate mRNA Translation Fate Through P-Body Dynamics

Nicolini, V. J.; Dupart, M.; Raffelsberger, W.; Vidal-Cruchez, O.; Rete, T.; Jacquet, K.; Brau, F.; Abelanet, S.; Irondelle, M.; Bourdin, A.; Durivault, J.; Gotorbe, C.; Knittel-Obrecht, A.; Didier, B.; Villa, P.; Di Gorgio, C.; Mograbi, B.; Hubstenberger, A.; Hofman, P.; Brest, P.

doi:10.1101/2025.10.30.685488

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bioRxiv · 10.1101/2025.10.30.685488

Glucocorticoids Modulate mRNA Translation Fate Through P-Body Dynamics

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Abstract

Processing bodies (P-bodies) are cytoplasmic, membraneless organelles that play a key role in regulating RNA translation. To identify new pathways controlling their formation, we conducted a Food and Drug Administration (FDA)-approved drug screen. We found that glucocorticoids, among the most prescribed medicines, significantly increase P-body numbers across diverse epithelial cell types. This effect was fully reversible after glucocorticoid withdrawal, illustrating the adaptive dynamics of P-bodies. Using genetic invalidation and rescue approaches, we demonstrated that this accumulation requires the Glucocorticoid Receptor alpha isoform. P-body accumulation was associated with the sequestration of P-body-specific-targeted mRNAs, altering their translation yield. Notably, this translational regulation depends on transcript sequence features rather than abundance, with AU-rich mRNA transcripts being sequestered and GC-rich mRNAs preferentially translated under glucocorticoid treatment. Furthermore, we linked the decrease of LSM14B, a negative regulator of P-bodies, under glucocorticoid treatment to P-body reshaping. Our results reveal that, beyond their known transcriptional activity, prolonged exposure to glucocorticoids influences mRNA post-transcription and translation through a nucleotide composition-based mechanism.

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Nicolini, V. J., Dupart, M., Raffelsberger, W., Vidal-Cruchez, O., Rete, T., Jacquet, K., Brau, F., Abelanet, S., Irondelle, M., Bourdin, A., Durivault, J., Gotorbe, C., Knittel-Obrecht, A., Didier, B., Villa, P., Di Gorgio, C., Mograbi, B., Hubstenberger, A., Hofman, P., Brest, P.. 2025-10-31. Glucocorticoids Modulate mRNA Translation Fate Through P-Body Dynamics. https://doi.org/10.1101/2025.10.30.685488

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