Alessia Ruggieri, PhD
Department of Infectious Diseases
Centre for Integrative Infectious Disease Research (CIID)
University of Heidelberg
Stress granules (SGs) form in the cytosol of mammalian cells in response to environmental imbalances and activation of the integrated stress response (ISR), a central signalling pathway controlling protein synthesis. To prevent sustained damage, the ISR is counteracted by a negative feedback loop via 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. Using infection with hepatitis C virus as model of chronic stress, we previously uncovered a unique temporal control of the ISR resulting in alternating phases of SG assembly and disassembly, which coincide with phases of stalled and active translation, respectively. By integrating quantitative experiments with mathematical modelling, we elucidated the molecular network generating this dynamic stress response. We demonstrated that stochastic bursts of GADD34 expression and rapid GADD34 protein turnover are important determinants of this unique temporal control. Furthermore, we identified GADD34 mRNA turnover as a key to the establishment of the ISR molecular memory, which sets the threshold for cellular responsiveness and mediates adaptation to stress.