In addition to responding to bacteria and viruses by detecting pathogen-associated molecular patterns, macrophages are also activated by host-derived, damage-associated molecular patterns (DAMPs). One such DAMP is chromosomal DNA released from apoptotic cells, which is usually taken up by macrophages and degraded by DNase II. Noting that mice deficient in DNase II produce excessive amounts of interferon-β (IFN-β) and CXCL10 when exposed to undigested DNA, Okabe et al. screened a mouse embryonic fibroblast cDNA library for candidates that could enhance this response. The authors identified Eyes absent 4 (EYA4), a transcriptional coactivator with tyrosine phosphatase activity, as a factor that, when overexpressed in transfected DNase II–deficient cells, enhanced their production of IFN-β and CXCL10 in response to DNA. EYA4 also enhanced the responses of transfected wild-type cells infected with various viruses compared with those of control-transfected cells but did not enhance responses to stimulation of cell-surface Toll-like receptors (TLRs). Analysis of mutant forms of EYA4 showed that, in addition to the tyrosine phosphatase activity associated with its C-terminal half, EYA4 possessed threonine phosphatase activity associated with its N-terminal region. Furthermore, mutations that abrogated its threonine phosphatase activity, but not those that prevented its tyrosine phosphatase activity, blocked the ability of EYA4 to enhance innate immune responses in transfected cells. In addition, EYA4 physically interacted with some cytosolic factors that are involved in the detection of nucleic acids, such as IPS-1. Together, these data suggest that EYA4 plays a cytosolic role in the innate immune response by regulating the threonine phosphorylation status of signaling molecules involved in this response.
Y. Okabe, T. Sano, S. Nagata, Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature 460, 520–524 (2009).[PubMed]