Translation repression via modulation of the cytoplasmic poly(A)-binding protein in the inflammatory response

  • Zhang X
  • Chen X
  • Liu Q
  • et al.
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Abstract

Gene expression is precisely regulated during the inflammatory response to control infection and limit the detrimental effects of inflammation. Here, we profiled global mRNA translation dynamics in the mouse primary macrophage-mediated inflammatory response and identified hundreds of differentially translated mRNAs. These mRNAs’ 3’UTRs have enriched binding motifs for several RNA-binding proteins, which implies extensive translational regulatory networks. We characterized one such protein, Zfp36, as a translation repressor. Using primary macrophages from a Zfp36-V5 epitope tagged knock-in mouse generated by CRISPR/Cas9-mediated genome editing, we found that the endogenous Zfp36 directly interacts with the cytoplasmic poly(A)-binding protein. Importantly, this interaction is required for the translational repression of Zfp36’s target mRNAs in resolving inflammation. Altogether, these results uncovered critical roles of translational regulations in controlling appropriate gene expression during the inflammatory response and revealed a new biologically relevant molecular mechanism of translational repression via modulating the cytoplasmic poly(A)-binding protein.DNA sequences called genes produce RNA molecules, some of which (the “messenger RNAs”) go on to be ‘translated’ to make proteins. This gene activity enables cells to react to their surroundings. For example, immune cells called macrophages produce hundreds of RNA molecules and proteins as part of an inflammatory response that defends the body against an infection. However, many of these molecules can also damage healthy tissue, so many layers of regulation control when, and how much of, these molecules are made.There are several ways to control how many proteins a cell produces. For example, cells might regulate how many messenger RNA molecules (also called mRNAs for short) are produced from a gene, or control how many proteins are translated from those mRNA molecules. Previous studies of how inflammatory responses are regulated have largely focussed on how mRNA production is controlled. Much less is known about the role that regulating mRNA translation has on the inflammatory response.By studying mouse macrophages, Zhang, Chen et al. have now identified hundreds of proteins whose production is regulated during an inflammatory response by controlling their translation from mRNA molecules. A group of RNA-binding proteins produced by the macrophages perform this regulation. Further observation revealed that a particular RNA-binding protein called Zfp36 prevents the translation of several important mRNAs, thereby helping to end an inflammatory response.Zhang, Chen et al. then genetically engineered mice to produce a version of Zfp36 that has a ‘tag’ attached to it that makes the protein easier to detect. Studying the activity of Zfp36 in these mice revealed that this RNA-binding protein works by interacting with another protein that normally binds to structures known as poly(A) tails at the end of the mRNA molecules.Zhang, Chen et al. believe that similar genetic engineering approaches could help researchers to study how other RNA-binding proteins work in living animals. In addition, by better understanding how inflammatory responses are regulated it may be possible to investigate new ways of treating conditions where this response is prolonged, such as in autoimmune disorders like rheumatoid arthritis.

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Zhang, X., Chen, X., Liu, Q., Zhang, S., & Hu, W. (2017). Translation repression via modulation of the cytoplasmic poly(A)-binding protein in the inflammatory response. ELife, 6. https://doi.org/10.7554/elife.27786

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