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Regulation of the innate immune response by threonine-phosphatase of Eyes absent

Nature volume 460, pages 520–524 (2009)Cite this article

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Abstract

Innate immunity is stimulated not only by viral or bacterial components, but also by non-microbial danger signals (damage-associated molecular patterns)1. One of the damage-associated molecular patterns is chromosomal DNA that escapes degradation. In programmed cell death and erythropoiesis, DNA from dead cells or nuclei expelled from erythroblasts is digested by DNase II in the macrophages after they are engulfed. DNase II-/- (also known as Dnase2a-/- ) mice suffer from severe anaemia or chronic arthritis due to interferon-β (IFN-β) and tumour necrosis factor-α (TNF-α) produced from the macrophages carrying undigested DNA2,3 in a Toll-like receptor (TLR)-independent mechanism4. Here we show that Eyes absent 4 (EYA4), originally identified as a co-transcription factor, stimulates the expression of IFN-β and CXCL10 in response to the undigested DNA of apoptotic cells. EYA4 enhanced the innate immune response against viruses (Newcastle disease virus and vesicular stomatitis virus), and could associate with signalling molecules (IPS-1 (also known as MAVS), STING (TMEM173) and NLRX1). Three groups have previously shown that EYA has phosphatase activity5,6,7. We found that mouse EYA family members act as a phosphatase for both phosphotyrosine and phosphothreonine. The haloacid dehalogenase domain at the carboxy terminus contained the tyrosine-phosphatase, and the amino-terminal half carried the threonine-phosphatase. Mutations of the threonine-phosphatase, but not the tyrosine-phosphatase, abolished the ability of EYA4 to enhance the innate immune response, suggesting that EYA regulates the innate immune response by modulating the phosphorylation state of signal transducers for the intracellular pathogens.

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Figure 1: Identification of EYA4 as a regulator for innate immunity.
Figure 2: Activation of the signalling cascade by EYA4.
Figure 3: Two different phosphatase activities in mouse EYA.
Figure 4: The threonine-phosphatase activity of EYA4 is required for the innate immune reaction.

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Change history

  • 23 July 2009

    The figure key for Figure 2a was corrected on 23 July 2009.

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Acknowledgements

We thank T. Fujita and M. Yoneyama for the NDV, A. Sehara-Fujisawa for the myogenin promoter, and M. Fujii and M. Harayama for secretarial assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture in Japan. T.S. is a Research Assistant for Kyoto University Global COE program (Center for Frontier Medicine).

Author Contributions Y.O. screened the cDNA library, and identified EYA4 as a regulator of the innate immune reaction. T.S. produced recombinant EYA in 293T cells and wheat-germ extracts, biochemically characterized, and found its threonine-phosphatase activity. S.N. designed the research and wrote the paper.

Author information

Author notes

  1. Yasutaka Okabe

    Present address: Present address: Department of Immunobiology, Yale University School of Medicine, TAC S-669, 300 Cedar Street, New Haven, Connecticut 06510, USA.,

  2. Yasutaka Okabe and Teruyuki Sano: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan,

    Yasutaka Okabe, Teruyuki Sano & Shigekazu Nagata

  2. Solution Oriented Research for Science and Technology, and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kyoto 606-8501, Japan

    Yasutaka Okabe & Shigekazu Nagata

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Correspondence to Shigekazu Nagata.

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Okabe, Y., Sano, T. & Nagata, S. Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature 460, 520–524 (2009). https://doi.org/10.1038/nature08138

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