GADD34 mRNA turnover controls the molecular memory of cellular stress experience

Abstract

SummaryThe integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of Growth Arrest and DNA Damage inducible 34 (GADD34), a stress- induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory step at the level of GADD34 mRNA post-transcriptional modification. We established that GADD34 mRNA 3’ untranslated region contains an active AU-rich element recognized by proteins of the ZFP36 family, which promotes its rapid decay under normal conditions and stabilization for efficient expression of GADD34 protein in response to stress. We identify the tight temporal control of GADD34 mRNA turnover as a central element of the ISR molecular memory, which sets the threshold for cellular responsiveness and mediates adaptation to recurring and chronic stress conditions.