Phosphorylation of murine SAMHD1 regulates its antiretroviral activity

  • BACKGROUND: Human SAMHD1 is a triphosphohydrolase that restricts the replication of retroviruses, retroelements and DNA viruses in noncycling cells. While modes of action have been extensively described for human SAMHD1, only little is known about the regulation of SAMHD1 in the mouse. Here, we characterize the antiviral activity of murine SAMHD1 with the help of knockout mice to shed light on the regulation and the mechanism of the SAMHD1 restriction and to validate the SAMHD1 knockout mouse model for the use in future infectivity studies. RESULTS: We found that endogenous mouse SAMHD1 restricts not only HIV-1 but also MLV reporter virus infection at the level of reverse transcription in primary myeloid cells. Similar to the human protein, the antiviral activity of murine SAMHD1 is regulated through phosphorylation at threonine 603 and is limited to nondividing cells. Comparing the susceptibility to infection with intracellular dNTP levels and SAMHD1 phosphorylation in different cell types shows that both functions are important determinants of the antiviral activity of murine SAMHD1. In contrast, we found the proposed RNase activity of SAMHD1 to be less important and could not detect any effect of mouse or human SAMHD1 on the level of incoming viral RNA. CONCLUSION: Our findings show that SAMHD1 in the mouse blocks retroviral infection at the level of reverse transcription and is regulated through cell cycle-dependent phosphorylation. We show that the antiviral restriction mediated by murine SAMHD1 is mechanistically similar to what is known for the human protein, making the SAMHD1 knockout mouse model a valuable tool to characterize the influence of SAMHD1 on the replication of different viruses in vivo.

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Author:Sabine Wittmann, Rayk Behrendt, Kristin Eissmann, Bianca Volkmann, Dominique Jeanette ThomasORCiDGND, Thomas Ebert, Alexandra Cribier, Monsef Benkirane, Veit Hornung, Nerea Ferreirós BouzasORCiDGND, Thomas Gramberg
URN:urn:nbn:de:hebis:30:3-412869
DOI:https://doi.org/10.1186/s12977-015-0229-6
ISSN:1742-4690
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/26667483
Parent Title (English):Retrovirology
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2015/12/15
Date of first Publication:2015/12/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/08/24
Tag:HIV-1; MLV; SAMHD1 knockout mouse; SAMHD1 phosphorylation
Volume:12
Issue:103
Page Number:15
First Page:1
Last Page:15
Note:
© 2015 Wittmann et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the  Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
HeBIS-PPN:432173455
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Medizin / Medizin
Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0