PIAS1 potentiates the anti-EBV activity of SAMHD1 through SUMOylation

Kun Zhang,Renfeng Li,Farjana Saiada

doi:10.1186/s13578-021-00636-y

Kun Zhang, Renfeng Li + Show 1 more

Open Access

https://doi.org/10.1186/s13578-021-00636-y

Copy DOI

Abstract

BackgroundSterile alpha motif and HD domain 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that restricts the infection of a variety of RNA and DNA viruses, including herpesviruses. The anti-viral function of SAMHD1 is associated with its dNTPase activity, which is regulated by several 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 EBV replication remains unknown.ResultsIn 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 phosphorylated SAMHD1 can be SUMOylated by PIAS1 and SUMOylated SAMHD1 can also be phosphorylated by viral protein kinases. We showed that SUMOylation-deficient SAMHD1 loses its anti-EBV activity. Furthermore, we demonstrated that SAMHD1 is associated with EBV genome in a PIAS1-dependent manner.ConclusionOur study reveals that PIAS1 synergizes with SAMHD1 to inhibit EBV lytic replication through protein–protein interaction and SUMOylation.

Highlights

Sterile alpha motif and HD domain 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase that restricts the infection of a variety of RNA and DNA viruses, including herpesviruses
To determine whether Protein inhibitor of activated STAT1 (PIAS1) and/or other members of the PIAS family interact with SAMHD1 (Fig. 1A), we co-transfected SAMHD1 with individual PIAS construct into 293 T cells and performed co-immunoprecipitation (Co-IP) experiments (Fig. 1B)
Because PIAS1 contain two small ubiquitinrelated modifier (SUMO) interacting motifs (SIM) that can bind to SUMOylated proteins [37], the modified SAMHD1 may represent a SUMOylated form with a molecular weight of approximately 10 kDa higher than SAMHD1

Summary

Introduction

Sterile alpha motif and HD domain 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that restricts the infection of a variety of RNA and DNA viruses, including herpesviruses. The anti-viral function of SAMHD1 is associated with its dNTPase activity, which is regulated by several post-translational modifications, including phosphorylation, acetylation and ubiquitination. Our recent studies demonstrated that the E3 SUMO ligase PIAS1 functions as an Epstein-Barr virus (EBV) restriction factor. One recently discovered restriction factor is the Sterile alpha motif and HD domain 1 (SAMHD1) protein, which hydrolyzes deoxyribonucleoside triphosphates (dNTPs) to reduce the cellular dNTP pool required for viral infection and propagation. Phosphorylation of SAMHD1 by the conserved herpesvirus protein kinases [4,5,6,7] and cellular kinases CDK1 and CDK2 diminishes its anti-viral activity [3, 14,15,16]. SAMHD1 is acetylated on K405 by ARD1 to enhance its dNTPase activity [23]

Methods

Results

Discussion

Conclusion