School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
Center for RNA Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea.
Sci Rep. 2018 Jan 8;8(1):84. doi: 10.1038/s41598-017-18308-8.
The autoimmune disorder Aicardi-Goutières syndrome (AGS) is characterized by a constitutive type I interferon response. SAMHD1 possesses both dNTPase and RNase activities and mutations in SAMHD1 cause AGS; however, how SAMHD1-deficiency causes the type I interferon response in patients with AGS remains unknown. Here, we show that endogenous RNA substrates accumulated in the absence of SAMHD1 act as a major immunogenic source for the type I interferon response. Reconstitution of SAMHD1-negative human cells with wild-type but not RNase-defective SAMHD1 abolishes spontaneous type I interferon induction. We further identify that the PI3K/AKT/IRF3 signaling pathway is essential for the type I interferon response in SAMHD1-deficient human monocytic cells. Treatment of PI3K or AKT inhibitors dramatically reduces the type I interferon signatures in SAMHD1-deficient cells. Moreover, SAMHD1/AKT1 double knockout relieves the type I interferon signatures to the levels observed for wild-type cells. Identification of AGS-related RNA sensing pathway provides critical insights into the molecular pathogenesis of the type I interferonopathies such as AGS and overlapping autoimmune disorders.
自身免疫性疾病 Aicardi-Goutières 综合征（AGS）的特征是固有Ⅰ型干扰素反应。SAMHD1 具有 dNTP 酶和核糖核酸酶活性，SAMHD1 的突变导致 AGS；然而，SAMHD1 缺陷如何导致 AGS 患者的Ⅰ型干扰素反应尚不清楚。在这里，我们表明，缺乏 SAMHD1 时积累的内源性 RNA 底物是Ⅰ型干扰素反应的主要免疫原性来源。用野生型而非核糖核酸酶缺陷型 SAMHD1 重建 SAMHD1 阴性的人细胞可消除自发性Ⅰ型干扰素诱导。我们进一步确定，PI3K/AKT/IRF3 信号通路对于 SAMHD1 缺陷型人单核细胞中的Ⅰ型干扰素反应是必不可少的。PI3K 或 AKT 抑制剂的治疗显著降低了 SAMHD1 缺陷型细胞中的Ⅰ型干扰素特征。此外，SAMHD1/AKT1 双敲除将Ⅰ型干扰素特征降低到观察到的野生型细胞水平。AGS 相关 RNA 感应途径的鉴定为Ⅰ型干扰素病（如 AGS 和重叠自身免疫性疾病）的分子发病机制提供了重要的见解。
