Fig. 7: Model for the regulation of SAMHD1 antiviral activity by SUMOylation in non-dividing cells.

a Human SAMHD1 harbors three major SUMO-attachment sites: K595 and K622 undergo mono-SUMOylation, while K469 and K622 are targeted by SUMO chains, which accumulate upon inhibition of the proteasome. Human SAMHD1 also harbors the surface-exposed SIM2 sequence, which drives the modification of K595 by SUMO, likely with a preference for the SUMO2 isoform (S2). b In actively dividing cells, SAMHD1 is targeted by CDK/cyclin-mediated phosphorylation on T592 during the G1/S transition thereby losing its antiviral activity (✗, colored in blue). A fraction of SAMHD1 (smaller circle) is SUMOylated on K595 by the action of Ubc9. However, this modification appears insufficient to fully neutralize the effects of phosphorylation and rescue restriction. Upon mitotic exit, phosphorylation is reversed by host PPP family phosphatases. Our results show that SAMHD1 harboring dephosphorylated T592 is antivirally inactive if SUMO-conjugation to K595 is prevented. They also indicate that only the fraction of SAMHD1 that harbors SUMOylated K595 and dephosphorylated T592 (✓, colored in yellow) efficiently inhibits viral infection through a dNTPase-independent mechanism.