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

Abstract

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.

SAMHD1 … and Viral Ways around It

“…In an affinity purification and mass spectrometry approach, Bogdanow et al confirmed SAMHD1 as a target of HCMV pUL97 and of the homologous kinase U69 of HHV7 [114]. In addition, De Meo et al substantiated previous findings that SAMHD1 is also phosphorylated through induction of CDK2 upon HCMV infection [115].…”

“…In contrast, herpesviruses employ their conserved serine/threonine kinases to phosphorylate and inactivate SAMHD1 [ 73 , 74 , 75 ]. In addition, downregulation of SAMHD1 or its relocalization might be alternative ways to circumvent antiviral restriction [ 67 , 70 , 73 , 115 , 126 , 127 , 130 ]. The variety of the hitherto uncovered SAMHD1 countermeasures emphasizes the importance of the restriction factor SAMHD1 in antiviral immunity.…”

“…Hyeon and colleagues also analyzed SAMHD1 protein level and found that HCMV infection induces the proteasomal degradation of SAMHD1 via a Cullin2 E3 ubiquitin ligase complex [ 127 ]. In addition, De Meo et al found that the HCMV-induced phosphorylation of SAMHD1 leads to its cytosolic relocalization and suggested that this relocalization might represent a novel evasion mechanism by HCMV [ 115 ]. Of note, the innate DNA sensor and HCMV inhibitory factor IFI16 was also shown to be phosphorylated by pUL97, leading to its inactivation and relocalization in a similar manner [ 128 , 129 ].…”

PIAS1 Potentiates the Anti-viral Activity of SAMHD1 through SUMOylation

“…Vpx proteins bind to SAMHD1 and E3 ubiquitin ligase complex to promote SAMHD1 ubiquitination and proteasome-dependent degradation (11)(12)(13). Phosphorylation of SAMHD1 by the conserved herpesvirus protein kinases (4-7) and cellular kinases CDK1 and CDK2 diminishes its anti-viral activity (3,(14)(15)(16). Although earlier studies suggested that SAMHD1's deoxynucleotide triphosphohydrolase (dNTPase) activity is not regulated by phosphorylation, recent studies revealed that phosphorylation suppress the dNTPase activity to elevate the dNTP level for optimal viral DNA synthesis (6,(17)(18)(19)(20)(21)(22).…”

“…Although earlier studies suggested that SAMHD1's deoxynucleotide triphosphohydrolase (dNTPase) activity is not regulated by phosphorylation, recent studies revealed that phosphorylation suppress the dNTPase activity to elevate the dNTP level for optimal viral DNA synthesis (6,(17)(18)(19)(20)(21)(22). SAMHD1 phosphorylation has also been implicated in its re-localization to cytoplasm during viral infection (16). SAMHD1 is acetylated by the acetyltransferase ARD1 to enhance its dNTPase activity (23).…”