SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity

by Simone De Meo, Valentina Dell’Oste, Rosa Molfetta, Valentina Tassinari, Lavinia Vittoria Lotti, Simone Vespa, Benedetta Pignoloni, Daniela Angela Covino, Laura Fantuzzi, Roberta Bona, Alessandra Zingoni, Ilaria Nardone, Matteo Biolatti, Alessandra Coscia, Rossella Paolini, Monsef Benkirane, Fredrik Edfors, Tatyana Sandalova, Adnane Achour, John Hiscott, Santo Landolfo, Angela Santoni, Cristina Cerboni

SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.