PIAS1 Potentiates the Anti-viral Activity of SAMHD1 through SUMOylation

Abstract Background: Sterile alpha motif and HD domain 1 (SAMHD1) is a host restriction factor that suppresses the infection of a variety of RNA and DNA viruses, including herpesviruses. The anti-viral activity of SAMHD1 is finely tuned by post-translational modifications, including phosphorylation, acetylation and ubiquitination. Our recent studies also demonstrated that the E3 SUMO ligase PIAS1 functions as an Epstein-Barr virus (EBV) restriction factor. However, whether SAMHD1 is regulated by PIAS1 to restrict viral infection remains unknown.Results: In this study, we showed that PIAS1 interacts with SAMHD1 and promotes its SUMOylation. We identified three lysine residues (K469, K595 and K622) located on the surface of SAMHD1 as the major SUMOylation sites. We demonstrated that phosphorylation of SAMHD1 slightly promotes its SUMOylation by PIAS1 and SUMOylated SAMHD1 can still be phosphorylated by viral protein kinases. We further demonstrated that SUMOylation-deficient SAMHD1 loses its anti-EBV activity. Conclusion: Our study reveals that PIAS1-mediated SUMOylation of SAMHD1 enhances its anti-viral activity.