Interferon regulatory factor 6 differentially regulates toll-like receptor 2-dependent chemokine gene expression in epithelial cells

Kwa, Mei Qi, Nguyen, Thao, Huynh, Jennifer, Ramnath, Divya, De Nardo, Dominic, Lam, Pei Yeng, Reynolds, Eric C., Hamilton, John A., Sweet, Matthew J. and Scholz, Glen M. (2014) Interferon regulatory factor 6 differentially regulates toll-like receptor 2-dependent chemokine gene expression in epithelial cells. Journal of Biological Chemistry, 289 28: 19758-19768. doi:10.1074/jbc.M114.584540

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Author Kwa, Mei Qi
Nguyen, Thao
Huynh, Jennifer
Ramnath, Divya
De Nardo, Dominic
Lam, Pei Yeng
Reynolds, Eric C.
Hamilton, John A.
Sweet, Matthew J.
Scholz, Glen M.
Title Interferon regulatory factor 6 differentially regulates toll-like receptor 2-dependent chemokine gene expression in epithelial cells
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2014-07-11
Year available 2014
Sub-type Article (original research)
DOI 10.1074/jbc.M114.584540
Open Access Status File (Publisher version)
Volume 289
Issue 28
Start page 19758
End page 19768
Total pages 11
Place of publication Rockville, MD United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2015
Language eng
Abstract Epidermal and mucosal epithelial cells are integral to host defense. They not only act as a physical barrier but also utilize pattern recognition receptors, such as the Toll-like receptors (TLRs), to detect and respond to pathogens. Members of the interferon regulatory factor (IRF) family of transcription factors are key components of TLR signaling as they impart specificity to downstream responses. Although IRF6 is a critical regulator of epithelial cell proliferation and differentiation, its role in TLR signaling has not previously been addressed. We show here that IRF6 is activated by IRAK1 as well as by MyD88 but not by TRIF or TBK1. Co-immunoprecipitation experiments further demonstrated that IRF6 can interact with IRAK1. Gene silencing in epithelial cells along with gene promoter reporter assays showed that IRAK1 mediates TLR2-inducible CCL5 gene expression at least in part by promoting IRF6 activation. Conversely, IRAK1 regulated CXCL8 gene expression independently of IRF6, thus identifying a molecular mechanism by which TLR2 signaling differentially regulates the expression of specific chemokines in epithelial cells. Bioinformatics analysis and mutagenesis-based experiments identified Ser-413 and Ser-424 as key regulatory sites in IRF6. Phosphomimetic mutation of these residues resulted in greatly enhanced IRF6 dimerization and trans-activator function. Collectively, our findings suggest that, in addition to its importance for epithelial barrier function, IRF6 also contributes to host defense by providing specificity to the regulation of inflammatory chemokine expression by TLR2 in epithelial cells.
Keyword Chemokine
Epithelial cell
Inflammation
Toll-like receptor (TLR)
Transcription factor
Interferon regulatory factor (IRF)
Interleukin receptor-associated kinase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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