The receptor for activated C kinase 1 (RACK1) adaptor protein has been implicated in viral infection. However, whether RACK1 promotes in vivo viral infection in mammals remains unknown. Moreover, it remains elusive how RACK1 is engaged in antiviral innate immune signaling. In this study, we report that myeloid RACK1 deficiency does not affect the development and survival of myeloid cells under resting conditions but renders mice less susceptible to viral infection. RACK1-deficient macrophages produce more IFN-α and IFN-β in response to both RNA and DNA virus infection. In line with this, RACK1 suppresses transcriptional activation of type 1 IFN gene promoters in response to virus infection. Analysis of virus-mediated signaling indicates that RACK1 inhibits the phosphorylation of IRF3/7. Indeed, RACK1 interacts with IRF3/7, which is enhanced after virus infection. Further exploration indicates that virus infection triggers AMPK activation, which in turn phosphorylates RACK1 at Thr⁵⁰. RACK1 phosphorylation at Thr⁵⁰ enhances its interaction with IRF3/7 and thereby limits IRF3/7 phosphorylation. Thus, our results confirm that myeloid RACK1 promotes in vivo viral infection and provide insight into the control of type 1 IFN production in response to virus infection.

活化 C 激酶 1 (RACK1) 衔接蛋白的受体与病毒感染有关。然而，RACK1 是否促进哺乳动物体内病毒感染仍然未知。此外，RACK1 如何参与抗病毒先天免疫信号仍然难以捉摸。在这项研究中，我们报告说，髓系 RACK1 缺乏不会影响静息条件下髓系细胞的发育和存活，但会使小鼠不易受到病毒感染。RACK1 缺陷型巨噬细胞在响应 RNA 和 DNA 病毒感染时会产生更多的 IFN-α 和 IFN-β。与此一致，RACK1 抑​​制 1 型 IFN 基因启动子的转录激活以响应病毒感染。病毒介导的信号分析表明 RACK1 抑​​制 IRF3/7 的磷酸化。事实上，RACK1 与 IRF3/7 相互作用，病毒感染后增强。进一步的探索表明，病毒感染会触发 AMPK 激活，进而使 RACK1 在 Thr 处磷酸化⁵⁰ . RACK1 在 Thr ⁵⁰处的磷酸化增强了它与 IRF3/7 的相互作用，从而限制了 IRF3/7 的磷酸化。因此，我们的结果证实，髓系 RACK1 促进体内病毒感染，并提供了对病毒感染响应 1 型 IFN 产生的控制的见解。