SAMHD1 Phosphorylation at T592 Regulates Cellular Localization and S-phase Progression.

Stephanie Batalis,David A Ornelles,Leann C Rogers,Christopher H Mauney,Thomas Hollis,Wayne O Hemphill

doi:10.3389/fmolb.2021.724870

Stephanie Batalis, David A Ornelles + Show 4 more

Open Access

https://doi.org/10.3389/fmolb.2021.724870

Copy DOI

Journal: Frontiers in Molecular Biosciences	Publication Date: Aug 26, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: Wake Forest University

Abstract

SAMHD1 activity is regulated by a network of mechanisms including phosphorylation, oxidation, oligomerization, and others. Significant questions remain about the effects of phosphorylation on SAMHD1 function and activity. We investigated the effects of a SAMHD1 T592E phosphorylation mimic on its cellular localization, catalytic activity, and cell cycle progression. We found that the SAMHD1 T592E is a catalytically active enzyme that is inhibited by protein oxidation. SAMHD1 T592E is retained in the nucleus at higher levels than the wild-type protein during growth factor-mediated signaling. This nuclear localization protects SAMHD1 from oxidation by cytoplasmic reactive oxygen species. The SAMHD1 T592E phosphomimetic further inhibits the cell cycle S/G2 transition. This has significant implications for SAMHD1 function in regulating innate immunity, antiviral response and DNA replication.

Highlights

SAMHD1 is a dNTP triphosphohydrolase that hydrolyzes the alpha linkage of dNTPs (Goldstone et al, 2011; Powell et al, 2011)
Given that SAMHD1 has been previously shown to translocate from the nucleus in response to growth factor signaling, and that post-translational modifications can be involved in protein trafficking, we tested the potential effects of T592 phosphorylation on SAMHD1 cellular localization
We demonstrate a link between SAMHD1 phosphorylation, cellular localization, and protein oxidation

Summary

Introduction

SAMHD1 is a dNTP triphosphohydrolase (dNTPase) that hydrolyzes the alpha linkage of dNTPs (Goldstone et al, 2011; Powell et al, 2011). It has emerged as a central component of several critical biological functions that depend on dNTP regulation, such as DNA replication and repair, cell cycle progression, and regulation of the innate immune response (Mauney and Hollis, 2018). In order to coordinate its diverse biological roles, SAMHD1 activity is regulated by several orthogonal mechanisms including protein tetramerization, phosphorylation, oxidation, acetylation, and sumoylation (Hofmann et al, 2012; White TE. et al, 2013; Cribier et al, 2013; Ji et al, 2013; Welbourn et al, 2013; Lee et al, 2017; Mauney et al, 2017; Wang et al, 2018; Martinat et al, 2020).

Methods

Results

Conclusion