1. Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan
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
3. Present address: Department of Immunobiology, Yale University School of Medicine, TAC S-669, 300 Cedar Street, New Haven, Connecticut 06510, USA.
4. These authors contributed equally to this work.

Correspondence to: Shigekazu Nagata^1,2 Correspondence and requests for materials should be addressed to S.N. (Email: snagata@mfour.med.kyoto-u.ac.jp).

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- (IFN-) and tumour necrosis factor- (TNF-) produced from the macrophages carrying undigested DNA^{2, 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- 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 activity^{5, 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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