ZBP1 regulates mRNA stability 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), which transiently associate with processing bodies (PBs), typically serving as mRNA decay centers. How mRNAs are protected from degradation in these structures remains elusive. We identify that Zipcode-binding protein 1 (ZBP1) regulates the cytoplasmic fate of specific mRNAs in nonstressed cells and is a key regulator of mRNA turnover during the ISR. ZBP1 association with target mRNAs in SGs was not essential for mRNA targeting to SGs. However, ZBP1 knockdown induced a selective destabilization of target mRNAs during the ISR, whereas forced expression increased mRNA stability. Our results indicate that although targeting of mRNAs to SGs is nonspecific, the stabilization of mRNAs during cellular stress requires specific protein-mRNA interactions. These retain mRNAs in SGs and prevent premature decay in PBs. Hence, mRNA-binding proteins are essential for translational adaptation during cellular stress by modulating mRNA turnover.
Stöhr
Nadine
N
NBL3 Research Group, Zentrum für Angewandte Medizinische und Humanbiologische Forschung, Department of Medicine, Martin-Luther-University, 06120 Halle, Germany.
Lederer
Marcell
M
Reinke
Claudia
C
Meyer
Sylke
S
Hatzfeld
Mechthild
M
Singer
Robert H
RH
Hüttelmaier
Stefan
S
D000818:Animals; D030161:Avian Proteins / Q000378:metabolism*; D002645:Chickens; D003594:Cytoplasmic Granules / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D021381:Protein Transport; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics
D030161:Avian Proteins; D016601:RNA-Binding Proteins; C498636:ZBP1 protein, Gallus gallus