Riess Maximilian, Fuchs Nina V, Idica Adam, Hamdorf Matthias, Flory Egbert, Pedersen Irene Munk, König Renate
From the Host-Pathogen Interactions Group and.
the Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697.
J Biol Chem. 2017 Jan 6;292(1):264-277. doi: 10.1074/jbc.M116.752584. Epub 2016 Dec 1.
SAMHD1 is a phosphohydrolase maintaining cellular dNTP homeostasis but also acts as a critical regulator in innate immune responses due to its antiviral activity and association with autoimmune disease, leading to aberrant activation of interferon. SAMHD1 expression is differentially regulated by interferon in certain primary cells, but the underlying mechanism is not understood. Here, we report a detailed characterization of the promotor region, the 5'- and 3'-untranslated region (UTR) of SAMHD1, and the mechanism responsible for the cell type-dependent up-regulation of SAMHD1 protein by interferon. We demonstrate that induction of SAMHD1 by type I and II interferons depends on 3'-UTR post-transcriptional regulation, whereas the promoter drives basal expression levels. We reveal novel functional target sites for the microRNAs miR-181a, miR-30a, and miR-155 in the SAMHD1 3'-UTR. Furthermore, we demonstrate that down-regulation of endogenous miR-181a and miR-30a levels inversely correlates with SAMHD1 protein up-regulation upon type I and II interferon stimulation in primary human monocytes. These miRNAs are not modulated by interferon in macrophages or dendritic cells, and consequently protein levels of SAMHD1 remain unchanged. These results suggest that SAMHD1 is a non-classical interferon-stimulated gene regulated through cell type-dependent down-regulation of miR-181a and miR-30a in innate sentinel cells.
SAMHD1是一种磷酸水解酶，可维持细胞内脱氧核苷酸三磷酸（dNTP）的稳态，同时因其抗病毒活性以及与自身免疫性疾病的关联，在先天免疫反应中作为关键调节因子，导致干扰素异常激活。在某些原代细胞中，SAMHD1的表达受干扰素的差异调节，但其潜在机制尚不清楚。在此，我们报告了SAMHD1启动子区域、5'和3'非翻译区（UTR）的详细特征，以及干扰素导致SAMHD1蛋白在细胞类型依赖性上调的机制。我们证明，I型和II型干扰素对SAMHD1的诱导依赖于3'UTR的转录后调控，而启动子驱动基础表达水平。我们揭示了SAMHD1 3'UTR中微小RNA miR-181a、miR-30a和miR-155的新功能靶位点。此外，我们证明，在原代人单核细胞中，I型和II型干扰素刺激后，内源性miR-181a和miR-30a水平的下调与SAMHD1蛋白的上调呈负相关。在巨噬细胞或树突状细胞中，这些微小RNA不受干扰素调节，因此SAMHD1的蛋白水平保持不变。这些结果表明，SAMHD1是一种非经典的干扰素刺激基因，在先天哨兵细胞中通过细胞类型依赖性下调miR-181a和miR-30a进行调控。
