Abstract
BackgroundHuman SAMHD1 possesses dual enzymatic functions. It acts as both a dGTP-dependent triphosphohydrolase and as an exoribonuclease. The dNTPase function depletes the cellular dNTP pool, which is required for retroviral reverse transcription in differentiated myeloid cells and resting CD4+ T cells; thus this activity mainly plays a role in SAMHD1-mediated retroviral restriction. However, a recent study demonstrated that SAMHD1 directly targets HIV-1 genomic RNA via its RNase activity, and that this function (rather than dNTPase activity) is sufficient for HIV-1 restriction. While HIV-1 genomic RNA is a potent target for SAMHD1 during viral infection, the specificity of SAMHD1-mediated RNase activity during infection by other viruses is unclear.ResultsThe results of the present study showed that SAMHD1 specifically degrades retroviral genomic RNA in monocyte-derived macrophage-like cells and in primary monocyte-derived macrophages. Consistent with this, SAMHD1 selectively restricted retroviral replication, but did not affect the replication of other common non-retro RNA genome viruses, suggesting that the RNase-mediated antiviral function of SAMHD1 is limited to retroviruses. In addition, neither inhibiting reverse transcription by treatment with several reverse transcriptase inhibitors nor infection with reverse transcriptase-defective HIV-1 altered RNA levels after viral challenge, indicating that the retrovirus-specific RNase function is not dependent on processes associated with retroviral reverse transcription.ConclusionsThe results presented herein suggest that the RNase activity of SAMHD1 is sufficient to control the replication of retroviruses, but not that of non-retro RNA viruses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0174-4) contains supplementary material, which is available to authorized users.
Highlights
SAMHD1 restricts a number of retroviruses by degrading genomic RNA The dual deoxynucleotide triphosphohydrolase (dNTPase) and RNase functions of SAMHD1 play a role in its anti-retroviral function
In a previous study [22], we generated SAMHD1 mutants showing either dNTPase or RNase activity to identify the contribution of RNase activity to human immunodeficiency virus-type 1 (HIV-1) restriction
The corresponding SAMHD1-expressing U937 cells were infected with Vesicular stomatitis virus (VSV)-G-pseudotyped reporter HIV-1, and the percentage of green fluorescent protein (GFP)-positive cells was evaluated by flow cytometry analysis (Additional file 1: Figure S1)
Summary
Occurring mutations in AGS-related proteins are closely linked to inappropriate accumulation of intrinsic self-derived nucleic acids and aberrant sensing of nucleic acids, which triggers immune activation via up-regulation of type I interferon (type I IFN) signaling. AGS is caused by mutations in the samhd gene In this context, it is hypothesized that the sterile alpha motif (SAM) and SAMHD1 was first identified as a deoxyguanosine triphosphate (dGTP)-dependent deoxynucleotide triphosphohydrolase (dNTPase) [5], a function mediated entirely by the HD domain [6]. The phosphorylation status of SAMHD1 on residue T592 affects its anti-retroviral function [18], it does not interfere with its dNTPase activity [19, 20] Taken together, these observations suggest that SAMHD1-mediated control of HIV-1 might not occur entirely in a dNTPase-dependent manner
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