IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs
- Cleveland Clinic, United States
- Stanford University School of Medicine, United States
- Zentrum für Molekulare Biologie der Universität Heidelberg, Germany
- Bristol-Myers Squibb, United States
- Shanghai Jiao Tong University School of Medicine, China
- Case Western Reserve University, United States
Abstract
Expression of inflammatory genes is determined in part by post-transcriptional regulation of mRNA metabolism but how stimulus- and transcript-dependent nuclear export influence is poorly understood. Here we report a novel pathway in which LPS/TLR4 engagement promotes nuclear localization of IRAK2 to facilitate nuclear export of a specific subset of inflammation related mRNAs for translation in murine macrophages. IRAK2 kinase activity is required for LPS-induced RanBP2-mediated IRAK2 sumoylation and subsequent nuclear translocation. Array analysis showed that an SRSF1 binding motif is enriched in mRNAs dependent on IRAK2 for nuclear export. Nuclear IRAK2 phosphorylates SRSF1 to reduce its binding to target mRNAs, which promotes the RNA binding of the nuclear export adaptor ALYREF and nuclear export receptor Nxf1 loading for the export of the mRNAs. In summary, LPS activates a nuclear function of IRAK2 that facilitates the assembly of nuclear export machinery to export selected inflammatory mRNAs to the cytoplasm for translation.
Article and author information
Author details
Funding
National Multiple Sclerosis Society (RG5130A2/1)
- Xiaoxia Li
National Institutes of Health (2PO1HL029582)
- Xiaoxia Li
American Diabetes Association (Postdoctoral Research Fellow Award,1-16-PDF-138)
- Hao Zhou
National Science Centre, Poland (2015/19/B/NZ6/01578)
- Katarzyna Bulek
National Institutes of Health (PO1CA062220)
- Xiaoxia Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Feng Shao, National Institute of Biological Sciences, China
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All procedures using animals were approved by the Cleveland Clinic Institutional Animal Care and Use Committee (Protocol Number: 2014-1229 and 2017-1814) .
Version history
- Received: June 15, 2017
- Accepted: October 6, 2017
- Accepted Manuscript published: October 9, 2017 (version 1)
- Version of Record published: November 7, 2017 (version 2)
Copyright
© 2017, Zhou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs
eLife 6:e29630.
https://doi.org/10.7554/eLife.29630
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