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

• Main Authors: Stephanie Batalis, LeAnn C. Rogers, Wayne O. Hemphill, Christopher H. Mauney, David A. Ornelles, Thomas Hollis
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-08-01
• Series: Frontiers in Molecular Biosciences
• Subjects: SAMHD1; phosphorylation; protein localization; protein oxidation; cell cycle; dNTP
• Online Access: https://www.frontiersin.org/articles/10.3389/fmolb.2021.724870/full

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.