HU 1547/3-1: The control of mRNA fate during cellular stress

An essential constituent of the integrated stress response (ISR) is a reversible translational suppression. This mRNA silencing occurs in distinct cytoplasmic foci called stress granules (SGs) that transiently associate with processing bodies (PBs) typically serving as mRNA decay centers. How mRNAs are protected from degradation in SGs remains largely elusive. In recent studies we discovered that the RNA-binding Zipcode-binding protein 1 (ZBP1), typically involved in regulating the cytoplasmic fate of specific mRNAs in nonstressed cells, is a key regulator of mRNA turnover when localized to SGs during the ISR. The association of ZBP1 with target mRNAs in SGs is not essential for mRNA-targeting to these cytoplasmic foci. However, ZBP1 knock-down induced a selective destabilization of target mRNAs during the ISR, while forced expression increased mRNA stability. With the projects proposed, we aim to identify the molecular networks via which ZBP1 and other RNA-binding proteins localized to SGs facilitate the regulation of mRNA fate during the ISR. The identification of these will set the stage to characterize how RNA-metabolism is controlled by RNA-binding proteins during cellular stress. An essential constituent of the integrated stress response (ISR) is a reversible translational suppression. This mRNA silencing occurs in distinct cytoplasmic foci called stress granules (SGs) that transiently associate with processing bodies (PBs) typically serving as mRNA decay centers. How mRNAs are protected from degradation in SGs remains largely elusive. In recent studies we discovered that the RNA-binding Zipcode-binding protein 1 (ZBP1), typically involved in regulating the cytoplasmic fate of specific mRNAs in nonstressed cells, is a key regulator of mRNA turnover when localized to SGs during the ISR. The association of ZBP1 with target mRNAs in SGs is not essential for mRNA-targeting to these cytoplasmic foci. However, ZBP1 knock-down induced a selective destabilization of target mRNAs during the ISR, while forced expression increased mRNA stability. With the projects proposed, we aim to identify the molecular networks via which ZBP1 and other RNA-binding proteins localized to SGs facilitate the regulation of mRNA fate during the ISR. The identification of these will set the stage to characterize how RNA-metabolism is controlled by RNA-binding proteins during cellular stress.