title: Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response.
abstract: Aicardi-Goutières syndrome (AGS), a hereditary autoimmune disease, clinically and biochemically overlaps with systemic lupus erythematosus (SLE) and, like SLE, is characterized by spontaneous type I interferon (IFN) production. The finding that defects of intracellular nucleases cause AGS led to the concept that intracellular accumulation of nucleic acids triggers inappropriate production of type I IFN and autoimmunity. AGS can also be caused by defects of SAMHD1, a 3' exonuclease and deoxynucleotide (dNTP) triphosphohydrolase. Human SAMHD1 is an HIV-1 restriction factor that hydrolyzes dNTPs and decreases their concentration below the levels required for retroviral reverse transcription. We show in gene-targeted mice that also mouse SAMHD1 reduces cellular dNTP concentrations and restricts retroviral replication in lymphocytes, macrophages, and dendritic cells. Importantly, the absence of SAMHD1 triggered IFN-β-dependent transcriptional upregulation of type I IFN-inducible genes in various cell types indicative of spontaneous IFN production. SAMHD1-deficient mice may be instrumental for elucidating the mechanisms that trigger pathogenic type I IFN responses in AGS and SLE.
authors: Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors: Rayk
authors: R
authors: Behrendt
authors: Tina
authors: T
authors: Schumann
authors: Alexander
authors: A
authors: Gerbaulet
authors: Laura A
authors: LA
authors: Nguyen
authors: Nadja
authors: N
authors: Schubert
authors: Dimitra
authors: D
authors: Alexopoulou
authors: Ursula
authors: U
authors: Berka
authors: Stefan
authors: S
authors: Lienenklaus
authors: Katrin
authors: K
authors: Peschke
authors: Kathrin
authors: K
authors: Gibbert
authors: Sabine
authors: S
authors: Wittmann
authors: Dirk
authors: D
authors: Lindemann
authors: Siegfried
authors: S
authors: Weiss
authors: Andreas
authors: A
authors: Dahl
authors: Ronald
authors: R
authors: Naumann
authors: Ulf
authors: U
authors: Dittmer
authors: Baek
authors: B
authors: Kim
authors: Werner
authors: W
authors: Mueller
authors: Thomas
authors: T
authors: Gramberg
authors: Axel
authors: A
authors: Roers
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology; D003854:Deoxyribonucleotides / Q000378:metabolism; D005622:Friend murine leukemia virus / Q000378:metabolism / Q000502:physiology; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D048348:Reverse Transcription; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014158:Transcription, Genetic; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: D003854:Deoxyribonucleotides; C508032:Ifnar1 protein, mouse; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484281:Samhd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins
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