title: Phosphorylation of murine SAMHD1 regulates its antiretroviral activity.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany. sabine.wittmann@viro.med.uni-erlangen.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wittmann
authors.affiliation: Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. Rayk.Behrendt@tu-dresden.de.
authors.forename: Rayk
authors.initials: R
authors.lastname: Behrendt
authors.affiliation: Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany. kristin.eissmann@viro.med.uni-erlangen.de.
authors.forename: Kristin
authors.initials: K
authors.lastname: Eissmann
authors.affiliation: Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany. bianca.volkmann@viro.med.uni-erlangen.de.
authors.forename: Bianca
authors.initials: B
authors.lastname: Volkmann
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany. Thomas@med.uni-frankfurt.de.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany. ebert1987@gmail.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebert
authors.affiliation: Laboratoire de Virologie Moléculaire, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, 34000, France. alexandra.cribier@igh.cnrs.fr.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cribier
authors.affiliation: Laboratoire de Virologie Moléculaire, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, 34000, France. monsef.benkirane@igh.cnrs.fr.
authors.forename: Monsef
authors.initials: M
authors.lastname: Benkirane
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany. veit.hornung@uni-bonn.de.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany. ferreirosbouzas@em.uni-frankfurt.de.
authors.forename: Nerea Ferreirós
authors.initials: NF
authors.lastname: Bouzas
authors.affiliation: Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany. thomas.gramberg@viro.med.uni-erlangen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gramberg
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009052:Leukemia Virus, Murine / Q000502:physiology*; D008264:Macrophages / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022423:Myeloid Cells / Q000821:virology; D010766:Phosphorylation; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D012192:Retroviridae Infections / Q000821:virology*; D048348:Reverse Transcription; D000076106:SAM Domain and HD Domain-Containing Protein 1; D013912:Threonine / Q000502:physiology; D014779:Virus Replication
chemical_list: D012367:RNA, Viral; D013912:Threonine; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484281:Samhd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins