SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways
SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways
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DOI：
10.1073/pnas.1801213115
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发表时间：
2018-04-17
影响因子：
11.1
通讯作者：
Wu, Li
中科院分区：
文献类型：
--
作者：
Chen, Shuliang;Bonifati, Serena;Wu, Li
无菌 α 基序和含 HD 结构域的蛋白 1 (SAMHD1) 通过减少细胞内 dNTP 池来阻止逆转录病毒和某些 DNA 病毒的复制。尽管 SAMHD1 在调节先天免疫方面的功能和机制尚不清楚，但 SAMHD1 已被认为可以下调 IFN 和对病毒感染的炎症反应。在这里，我们发现 SAMHD1 通过抑制核因子 kappa B (NF-kappa B) 激活和 I 型干扰素 (IFN-I) 诱导来抑制对病毒感染和炎症刺激的先天免疫反应。与对照细胞相比，用仙台病毒 (SeV) 或 HIV-1 感染 SAMHD1 沉默的人单核细胞或原代巨噬细胞，或用炎症刺激物治疗，可诱导显着更高水平的 NF-κ B 激活和 IFN-I 诱导。细胞中的外源性 SAMHD1 表达或敲除细胞中的 SAMHD1 重建可抑制 SeV 感染或炎症刺激引起的 NF-κ B 激活和 IFN-I 诱导。从机制上讲，SAMHD1 通过与 NF-kappa B1/2 相互作用并减少 NF-kappa B 抑制蛋白 I kappa B α 的磷酸化来抑制 NF-kappa B 激活。 SAMHD1 还与抑制剂 kappa B 激酶 epsilon (IKK epsilon) 和 IFN 调节因子 7 (IRF7) 相互作用，通过减少 IKK epsilon 介导的 IRF7 磷酸化来抑制 IFN-I 诱导途径。内源性 SAMHD1 与 NF-κ B 和 IFN-I 通路蛋白的相互作用在人单核细胞和原代巨噬细胞中得到验证。比较 SAMHD1 敲除小鼠和杂合子小鼠的脾细胞，我们进一步证实了 SAMHD1 介导的 NF-κ B 激活抑制，表明 SAMHD1 具有进化上保守的特性。我们的研究结果揭示了 SAMHD1 在下调病毒感染和炎症刺激的先天免疫反应中的功能，强调了 SAMHD1 在调节抗病毒免疫中的重要性。
Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) blocks replication of retroviruses and certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN and inflammatory responses to viral infections, although the functions and mechanisms of SAMHD1 in modulating innate immunity remain unclear. Here, we show that SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-kappa B (NF-kappa B) activation and type I interferon (IFN-I) induction. Compared with control cells, infection of SAMHD1-silenced human monocytic cells or primary macrophages with Sendai virus (SeV) or HIV-1, or treatment with inflammatory stimuli, induces significantly higher levels of NF-kappa B activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-kappa B activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-kappa B activation by interacting with NF-kappa B1/2 and reducing phosphorylation of the NF-kappa B inhibitory protein I kappa B alpha. SAMHD1 also interacts with the inhibitor-kappa B kinase epsilon (IKK epsilon) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKK epsilon-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-kappa B and IFN-I pathway proteins were validated in human monocytic cells and primary macrophages. Comparing splenocytes from SAMHD1 knockout and heterozygous mice, we further confirmed SAMHD1-mediated suppression of NF-kappa B activation, suggesting an evolutionarily conserved property of SAMHD1. Our findings reveal functions of SAMHD1 in down-regulating innate immune responses to viral infections and inflammatory stimuli, highlighting the importance of SAMHD1 in modulating antiviral immunity.