Abstract
SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation. Here, we show that SAMHD1 dephosphorylation at T592 is controlled during the cell cycle, occurring during M/G1 transition in proliferating cells. Using several complementary proteomics and biochemical approaches, we identify the phosphatase PP2A-B55α responsible for rendering SAMHD1 antivirally active. SAMHD1 is specifically targeted by PP2A-B55α holoenzymes during mitotic exit, in line with observations that PP2A-B55α is a key mitotic exit phosphatase in mammalian cells. Strikingly, as HeLa or activated primary CD4+ T cells enter the G1 phase, pronounced reduction of RT products is observed upon HIV-1 infection dependent on the presence of dephosphorylated SAMHD1. Moreover, PP2A controls SAMHD1 pT592 level in non-cycling monocyte-derived macrophages (MDMs). Thus, the PP2A-B55α holoenzyme is a key regulator to switch on the antiviral activity of SAMHD1.
Highlights
SAMHD1 is a critical restriction factor for human immunodeficiency virus (HIV)-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation
SAMHD1 phosphorylation at T592 appeared high in early S phase (0–4 h post-release)—consistent with reports of initial CDK2-dependent phosphorylation at T59224,30
After maximal activity of cyclin-dependent kinase (CDK)/cyclin A2, SAMHD1 phosphorylation is maintained in G2/M phase (7–8 h postrelease)—accompanied by maximal cyclin A2/B1 expression (Fig. 1a)
Summary
SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation. Besides the control of SAMHD1’s antiviral activity, phosphorylation at T592 has been proposed to play a novel role in promoting the resection of arrested replication forks and preventing the accumulation of single-stranded DNA (ssDNA) derived from stalled forks in the cytoplasm[29]. This reinforces the importance of both, phosphorylation and dephosphorylation at this specific residue, for diverse physiological functional states of SAMHD1
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