Beijing Institute of Basic Medical Sciences, Beijing, China.
Beijing Institute of Basic Medical Sciences, Beijing, China
J Immunol. 2021 Sep 1;207(5):1411-1418. doi: 10.4049/jimmunol.2100086. Epub 2021 Aug 4.
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 Thr RACK1 phosphorylation at Thr 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.
激活蛋白激酶 C 受体 1（RACK1）衔接蛋白已被牵涉到病毒感染中。然而，RACK1 是否在哺乳动物体内促进病毒感染仍不清楚。此外，RACK1 如何参与抗病毒先天免疫信号转导仍不清楚。在本研究中，我们报告髓系 RACK1 缺陷并不影响静止状态下髓系细胞的发育和存活，但使小鼠对病毒感染的敏感性降低。RACK1 缺陷型巨噬细胞在 RNA 和 DNA 病毒感染时产生更多的 IFN-α 和 IFN-β。与此一致的是，RACK1 抑制病毒感染后 1 型 IFN 基因启动子的转录激活。对病毒介导的信号转导分析表明，RACK1 抑制 IRF3/7 的磷酸化。事实上，RACK1 与 IRF3/7 相互作用，这种相互作用在病毒感染后增强。进一步的探索表明，病毒感染触发 AMPK 的激活，从而磷酸化 RACK1 的 Thr 位，增强其与 IRF3/7 的相互作用，从而限制 IRF3/7 的磷酸化。因此，我们的结果证实了髓系 RACK1 促进体内病毒感染，并为病毒感染后 1 型 IFN 产生的控制提供了新的见解。
