Abstract
The 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 mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We establish that the 3′ untranslated region of PPP1R15A mRNA contains an active AU-rich element (ARE) recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a component of the transient ISR memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.
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•Under normal conditions, TTP/Brf1 recognize PPP1R15A ARE promoting mRNA rapid decay•PPP1R15A mRNA turnover regulates the threshold at which the ISR is triggered•Cellular stress enhances PPP1R15A mRNA stability, favoring GADD34 translation•Decay of PPP1R15A mRNA enhances sensitivity to stress and antagonizes adaptation
Magg et al. uncover a novel regulatory step of the integrated stress response at the level of PPP1R15A mRNA stability and establish AU-rich element-driven mRNA turnover as an important determinant controlling GADD34 expression, thereby shaping the dynamics of stress adaptation and sensitivity to repetitive stress exposure.