INSERM Equipe Avenir, CNRS UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
PLoS One. 2012;7(8):e42725. doi: 10.1371/journal.pone.0042725. Epub 2012 Aug 15.
Innate immune responses against DNA are essential to counter both pathogen infections and tissue damages. Mammalian EYAs were recently shown to play a role in regulating the innate immune responses against DNA. Here, we demonstrate that the unique Drosophila eya gene is also involved in the response specific to DNA. Haploinsufficiency of eya in mutants deficient for lysosomal DNase activity (DNaseII) reduces antimicrobial peptide gene expression, a hallmark for immune responses in flies. Like the mammalian orthologues, Drosophila EYA features a N-terminal threonine and C-terminal tyrosine phosphatase domain. Through the generation of a series of mutant EYA fly strains, we show that the threonine phosphatase domain, but not the tyrosine phosphatase domain, is responsible for the innate immune response against DNA. A similar role for the threonine phosphatase domain in mammalian EYA4 had been surmised on the basis of in vitro studies. Furthermore EYA associates with IKKβ and full-length RELISH, and the induction of the IMD pathway-dependent antimicrobial peptide gene is independent of SO. Our data provide the first in vivo demonstration for the immune function of EYA and point to their conserved immune function in response to endogenous DNA, throughout evolution.
先天免疫反应针对 DNA 对于抵御病原体感染和组织损伤至关重要。最近发现哺乳动物的 EYA 蛋白在调节针对 DNA 的先天免疫反应中发挥作用。在这里，我们证明独特的果蝇 eya 基因也参与了针对 DNA 的特异性反应。在溶酶体 DNA 酶（DNaseII）活性缺陷的突变体中，eya 的单倍不足会降低抗菌肽基因的表达，这是果蝇免疫反应的一个标志。与哺乳动物同源物一样，果蝇 EYA 具有 N 端苏氨酸和 C 端酪氨酸磷酸酶结构域。通过生成一系列突变的 EYA 果蝇株系，我们表明，苏氨酸磷酸酶结构域，而不是酪氨酸磷酸酶结构域，负责针对 DNA 的先天免疫反应。基于体外研究推测了在哺乳动物 EYA4 中 threonine phosphatase 结构域具有类似的作用。此外，EYA 与 IKKβ 和全长 RELISH 相关，并且 IMD 途径依赖性抗菌肽基因的诱导不依赖于 SO。我们的数据首次提供了 EYA 在免疫功能方面的体内证据，并指出它们在整个进化过程中针对内源性 DNA 具有保守的免疫功能。
