Division of Immunology, Department of Microbiology & Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Immunity. 2011 Sep 23;35(3):426-40. doi: 10.1016/j.immuni.2011.06.014. Epub 2011 Sep 8.
To systematically investigate innate immune signaling networks regulating production of type I interferon, we analyzed protein complexes formed after microbial recognition. Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions; 21% of interactions were modulated by RNA, DNA, or LPS. Overexpression and depletion analyses identified 22 unique genes that regulated NF-κB and ISRE reporter activity, viral replication, or virus-induced interferon production. Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. Mib genes selectively controlled responses to cytosolic RNA. MIB deficiency reduced antiviral activity, establishing the role of MIB proteins as positive regulators of antiviral responses. The HI5 provides a dynamic physical and regulatory network that serves as a resource for mechanistic analysis of innate immune signaling.
为了系统地研究调节 I 型干扰素产生的先天免疫信号网络，我们分析了微生物识别后形成的蛋白质复合物。58 个诱饵与 260 个相互作用的蛋白质形成了一个人类先天免疫互作组，其中包含 401 个独特的相互作用；21%的相互作用受 RNA、DNA 或 LPS 调节。过表达和耗尽分析确定了 22 个独特的基因，它们调节 NF-κB 和 ISRE 报告基因活性、病毒复制或病毒诱导的干扰素产生。详细的机制分析定义了 MIB E3 连接酶在 TBK1 上 K63 连接泛素化中的作用，TBK1 是一种磷酸化 IRF 转录因子从而控制干扰素产生的激酶。Mib 基因选择性地控制对细胞质 RNA 的反应。MIB 缺陷降低了抗病毒活性，确立了 MIB 蛋白作为抗病毒反应的正调节剂的作用。HI5 提供了一个动态的物理和调节网络，作为先天免疫信号转导的机制分析的资源。
