The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids. Here we use an affinity proteomics approach in evolutionary distant species (human, mouse and fly) to identify proteins that are conserved in their ability to associate with diverse viral nucleic acids. This approach shows a core of orthologous proteins targeting viral genetic material and species-specific interactions. Functional characterization of the influence of 181 candidates on replication of 6 distinct viruses in human cells and flies identifies 128 nucleic acid binding proteins with an impact on virus growth. We identify the family of TAO kinases (TAOK1, −2 and −3) as dsRNA-interacting antiviral proteins and show their requirement for type-I interferon induction. Depletion of TAO kinases in mammals or flies leads to an impaired response to virus infection characterized by a reduced induction of interferon stimulated genes in mammals and impaired expression of srg1 and diedel in flies. Overall, our study shows a larger set of proteins able to mediate the interaction between viral genetic material and host factors than anticipated so far, attesting to the ancestral roots of innate immunity and to the lineage-specific pressures exerted by viruses.

多细胞生物的细胞内在抗病毒反应发展了数百万年，并且严重依赖于感知和消除病毒核酸的能力。在这里，我们在进化较远的物种（人类、小鼠和苍蝇）中使用亲和蛋白质组学方法来鉴定在与不同病毒核酸相关联的能力方面保守的蛋白质。这种方法显示了针对病毒遗传物质和物种特异性相互作用的直系同源蛋白的核心。181 种候选病毒对人类细胞和果蝇中 6 种不同病毒复制的影响的功能表征确定了 128 种对病毒生长有影响的核酸结合蛋白。我们将 TAO 激酶家族（TAOK1、-2 和 -3）鉴定为 dsRNA 相互作用的抗病毒蛋白，并显示它们对 I 型干扰素诱导的要求。果蝇中的srg1和diedel。总体而言，我们的研究表明，与目前预期相比，能够介导病毒遗传物质与宿主因子之间相互作用的蛋白质组数量更多，证明了先天免疫的祖先根源以及病毒施加的谱系特异性压力。