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

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

doi:10.1371/journal.ppat.1008855

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.

Highlights

Human cytomegalovirus (HCMV) is a widely diffused β-herpesvirus infecting most of the population worldwide
Some frontline proteins belonging to the innate immune system, known as restriction factors, are already
To study the role of SAMHD1 in HCMV infection, we first investigated if its expression was modulated at both mRNA and protein levels in different cell types

Summary

Introduction

Human cytomegalovirus (HCMV) is a widely diffused β-herpesvirus infecting most of the population worldwide. HCMV infection is not associated with disease, but in individuals with an immature or compromised immune system, it can be a serious and even lifethreatening pathogen [1]. HCMV disseminates throughout the body by replicating in a wide variety of cell types, including fibroblasts, epithelial and endothelial cells, macrophages and CD34+ progenitors, where it establishes a latent infection [2]. Several components of the innate immune system cooperate to limit the initial stages of HCMV replication and dissemination, representing the frontline antiviral defense of the host [3]. Host innate restriction factors (RFs) mediate a cell-intrinsic resistance that arrests the viral life cycle at specific steps of infection, replication, and maturation [3]. In relation to HCMV, the best characterized RFs are IFI16, viperin and members of the APOBEC3 family [4]

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Conclusion