SAMHD1 (Sterile Alpha Motif and Histidine-aspartate Domain containing protein 1) has been documented as a host factor that restricts HIV-1 and some DNA viruses. In this work, we attempted to explore possible effects of SAMHD1 on exogenous DNA and show that SAMHD1 exerts a general inhibition on the expression of exogenous DNA in vitro and in mice. This inhibition is achieved through repressing transcription of exogenous DNA. Intriguingly, unlike SAMHD1’s restriction of HIV-1, such restriction does not require the dNTPase or RNase activities, or T592 phosphorylation of SAMHD1. Mechanistically, SAMHD1 enhances the expression of interferon regulatory factor-1 (IRF1), while IRF1 upregulation was demonstrated to inhibit exogenous DNA expression in a similar fashion as SAMHD1. IFNλ1, whose induction has been associated with IRF1 activation, is dispensable for SAMHD1/IRF1-mediated restriction of exogenous DNA, and neither type I nor II interferons appear to be involved. We also demonstrate that SAMHD1/IRF1-mediated restriction can effectively inhibit hepatitis B virus (HBV) antigen expression and progeny virus production in mouse models. In conclusion, these data support restriction of exogenous DNA as a novel function of SAMHD1.

SAMHD1（S terile A lpha M otif and H istidine-aspartate D omain containing protein 1）已被记录为限制 HIV-1 和一些 DNA 病毒的宿主因子。在这项工作中，我们试图探索 SAMHD1 对外源 DNA 的可能影响，并表明 SAMHD1在体外对外源 DNA 的表达具有普遍的抑制作用在老鼠身上。这种抑制是通过抑制外源 DNA 的转录来实现的。有趣的是，与 SAMHD1 对 HIV-1 的限制不同，这种限制不需要 dNTPase 或 RNase 活性，或 SAMHD1 的 T592 磷酸化。从机制上讲，SAMHD1 增强了干扰素调节因子-1 (IRF1) 的表达，而 IRF1 上调被证明以与 SAMHD1 类似的方式抑制外源 DNA 表达。IFNλ1，其诱导与 IRF1 激活有关，对于 SAMHD1/IRF1 介导的外源 DNA 限制是可有可无的，并且 I 型和 II 型干扰素似乎都没有参与。我们还证明 SAMHD1/IRF1 介导的限制可以有效抑制小鼠模型中的乙型肝炎病毒 (HBV) 抗原表达和后代病毒产生。综上所述，