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Published online 13 November 2006. doi:10.1083/jcb.200608071
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 4, 527-534
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 ZBP1 regulates mRNA stability during cellular stress

Nadine Stöhr1, Marcell Lederer1, Claudia Reinke1, Sylke Meyer2, Mechthild Hatzfeld3, Robert H. Singer4, and Stefan Hüttelmaier1

1 NBL3 Research Group, Zentrum für Angewandte Medizinische und Humanbiologische Forschung, Department of Medicine, and 2 Department of Biochemistry, Martin-Luther-University, 06120 Halle, Germany
3 Institute for Pathophysiology, Division of Pathobiochemistry, Martin-Luther-University Halle, 06114 Halle, Germany
4 Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461

Correspondence to Stefan Hüttelmaier: stefan.huettelmaier{at}medizin.uni-halle.de

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.

Abbreviations used in this paper: BiFC, bimolecular fluorescent complementation; IGF, insulin-like growth factor; ISR, integrated stress response; MS2BP, MS2-binding protein; NLS, nuclear localization signal; PB, processing body; qRT-PCR, quantitative RT-PCR; RBP, RNA-binding protein; SG, stress granule; ZBP, Zipcode-binding protein.


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