Restriction of exogenous DNA expression by SAMHD1

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.