Restriction of exogenous DNA expression by SAMHD1

SAMHD1对外源DNA的限制作用

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. IFNk1, 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.

本研究发现宿主限制因子SAMHD1在体外培养细胞和小鼠体内都表现出抑制外源DNA表达的活性.其中, SAMHD1对外源DNA的抑制作用不依赖其d NTPase和RNase活性,而且SAMHD1可以特异地结合干扰素调节因子1(Irf1)基因的启动子区域,从而上调IRF1的表达水平而抑制外源DNA的表达.进一步的实验研究发现,SAMHD1/IRF1能够显著降低外源DNA上与转录活化相关的组蛋白修饰的水平,并且SAMHD1/IRF1抑制外源DNA的表达不依赖于干扰素途径.在乙型肝炎病毒(HBV)细胞感染模型和HBV重组ccc DNA(rccc DNA)小鼠模型中,我们也证实了SAMHD1/IRF1对HBV的抗原表达和复制存在显著的抑制作用.本研究发现了限制外源DNA的表达是SAMHD1的一个新功能.