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The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a β-catenin-dependent pathway

Abstract

Intracellular nucleic acid sensors detect microbial RNA and DNA and trigger the production of type I interferon. However, the cytosolic nucleic acid–sensing system remains to be fully identified. Here we show that the cytosolic nucleic acid–binding protein LRRFIP1 contributed to the production of interferon-β (IFN-β) induced by vesicular stomatitis virus (VSV) and Listeria monocytogenes in macrophages. LRRFIP1 bound exogenous nucleic acids and increased the expression of IFN-β induced by both double-stranded RNA and double-stranded DNA. LRRFIP1 interacted with β-catenin and promoted the activation of β-catenin, which increased IFN-β expression by binding to the C-terminal domain of the transcription factor IRF3 and recruiting the acetyltransferase p300 to the IFN-β enhanceosome via IRF3. Therefore, LRRFIP1 and its downstream partner β-catenin constitute another coactivator pathway for IRF3-mediated production of type I interferon.

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Figure 1: LRRFIP1 increases L. monocytogenes– and VSV–induced production of IFN-β in macrophages.
Figure 2: LRRFIP1 increases dsRNA- and dsDNA-induced expression of IFN-β in macrophages.
Figure 3: LRRFIP1 mediates L. monocytogenes– and VSV-induced activation of β-catenin.
Figure 4: Positive regulation by β-catenin of pathogen-induced production of IFN-β in macrophages.
Figure 5: Interaction between β-catenin and IRF3.
Figure 6: Binding of β-catenin to the Ifnb1 promoter locus though interaction with IRF3, which promotes p300 recruitment and acetylation of histones H3 and H4 at the Ifnb1 promoter locus.

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Acknowledgements

We thank X. Ma and T. Zuo for technical assistance; W. Pan (Second Military Medical University) for VSV; and H. Shen (University of Pennsylvania School of Medicine) for L. monocytogenes. Supported by the National Natural Science Foundation of China (30825036 and 30721091), the National Key Basic Research Program of China (2007CB512403), the National Grand Program on Key Infectious Disease (2009ZX10004-309) and the Program for New Century Excellent Talents in University of the Ministry of Education of China (NCET-07-0143).

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P.Y., H.A., X.L., M.W., Y.Z. and Y.R. did the experiments; and X.C. and H.A. designed the study and wrote the paper.

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Correspondence to Huazhang An or Xuetao Cao.

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Yang, P., An, H., Liu, X. et al. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a β-catenin-dependent pathway. Nat Immunol 11, 487–494 (2010). https://doi.org/10.1038/ni.1876

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