eLife (Oct 2017)
IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs
- Hao Zhou,
- Katarzyna Bulek,
- Xiao Li,
- Tomasz Herjan,
- Minjia Yu,
- Wen Qian,
- Han Wang,
- Gao Zhou,
- Xing Chen,
- Hui Yang,
- Lingzi Hong,
- Junjie Zhao,
- Luke Qin,
- Koichi Fukuda,
- Annette Flotho,
- Ji Gao,
- Ashok Dongre,
- Julie A Carman,
- Zizhen Kang,
- Bing Su,
- Timothy S Kern,
- Jonathan D Smith,
- Thomas A Hamilton,
- Frauke Melchior,
- Paul L Fox,
- Xiaoxia Li
Affiliations
- Hao Zhou
- ORCiD
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Katarzyna Bulek
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
- Xiao Li
- Department of Genetics, Stanford University School of Medicine, Stanford, United States
- Tomasz Herjan
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Minjia Yu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, United States
- Wen Qian
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Han Wang
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Gao Zhou
- Department of Genetics, Stanford University School of Medicine, Stanford, United States
- Xing Chen
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Hui Yang
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Lingzi Hong
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Junjie Zhao
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Luke Qin
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Koichi Fukuda
- Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Annette Flotho
- Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Alliance, Heidelberg, Germany
- Ji Gao
- Discovery Biology, Bristol-Myers Squibb, Princeton, United States
- Ashok Dongre
- Discovery Biology, Bristol-Myers Squibb, Princeton, United States
- Julie A Carman
- Discovery Biology, Bristol-Myers Squibb, Princeton, United States
- Zizhen Kang
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Bing Su
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Immunobiology, Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, United States
- Timothy S Kern
- School of Medicine, Case Western Reserve University, Cleveland, United States; Stokes Veterans Administration Hospital, Cleveland, United States
- Jonathan D Smith
- Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, United States
- Thomas A Hamilton
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- Frauke Melchior
- ORCiD
- Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Alliance, Heidelberg, Germany
- Paul L Fox
- Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, United States
- Xiaoxia Li
- ORCiD
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
- DOI
- https://doi.org/10.7554/eLife.29630
- Journal volume & issue
-
Vol. 6
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.
Keywords
