Abstract
Alterations in global mRNA decay broadly impact multiple stages of gene expression, although signals that connect these processes are incompletely defined. Here, we used tandem mass tag labeling coupled with mass spectrometry to reveal that changing the mRNA decay landscape, as frequently occurs during viral infection, results in subcellular redistribution of RNA binding proteins (RBPs) in human cells. Accelerating Xrn1-dependent mRNA decay through expression of a gammaherpesviral endonuclease drove nuclear translocation of many RBPs, including poly(A) tail-associated proteins. Conversely, cells lacking Xrn1 exhibited changes in the localization or abundance of numerous factors linked to mRNA turnover. Using these data, we uncovered a new role for relocalized cytoplasmic poly(A) binding protein in repressing recruitment of TATA binding protein and RNA polymerase II to promoters. Collectively, our results show that changes in cytoplasmic mRNA decay can directly impact protein localization, providing a mechanism to connect seemingly distal stages of gene expression.
Highlights
MRNA decay is a critical stage of gene expression that regulates the abundance and lifespan of cellular mRNAs
We show that the recruitment of TATA binding protein (TBP) to promoters is impaired in response to PABPC nuclear translocation, indicating that cytoplasmic mRNA decay impacts early events in preinitiation complex assembly
We previously demonstrated that muSOX expression in these cells activates the mRNA decay-RNA polymerase II (RNAPII) transcription feedback pathway similar to virally infected fibroblasts (Abernathy et al, 2015)
Summary
MRNA decay is a critical stage of gene expression that regulates the abundance and lifespan of cellular mRNAs. A drop in these molecules could act as an early warning of ill health in cells and trigger responses in the nucleus This new link between messenger RNA destruction and production may help to shed new light on how cells use different signals to control the production of their own genes while restricting pathogens from taking over. We charted global alterations in protein localization that occur in response to increased or decreased Xrn activity This revealed a set of mammalian RBPs that preferentially move from the cytoplasm to the nucleus during accelerated mRNA decay, as well as components of the 5’À3’ decay machinery and other RBPs whose subcellular distribution is altered in cells lacking Xrn. Our results reveal how mRNA levels exert significant influence on RBP localization and suggest that select RBPs transmit mRNA abundance information from the cytoplasm to the nucleus to broadly influence gene expression, under conditions of cellular stress
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