title: Phosphorylation of mouse SAMHD1 regulates its restriction of human immunodeficiency virus type 1 infection, but not murine leukemia virus infection.
abstract: Human SAMHD1 (hSAMHD1) restricts HIV-1 infection in non-dividing cells by depleting intracellular dNTPs to limit viral reverse transcription. Phosphorylation of hSAMHD1 at threonine (T) 592 by cyclin-dependent kinase (CDK) 1 and CDK2 negatively regulates HIV-1 restriction. Mouse SAMHD1 (mSAMHD1) restricts HIV-1 infection in non-dividing cells, but whether its phosphorylation regulates retroviral restriction is unknown. Here we identified six phospho-sites of mSAMHD1, including T634 that is homologous to T592 of hSAMHD1 and phosphorylated by CDK1 and CDK2. We found that wild-type (WT) mSAMHD1 and a phospho-ablative mutant, but not a phospho-mimetic mutant, restricted HIV-1 infection in differentiated U937 cells. Murine leukemia virus (MLV) infection of dividing NIH3T3 cells was modestly restricted by mSAMHD1 WT and phospho-mutants, but not by a dNTPase-defective mutant. Our results suggest that phosphorylation of mSAMHD1 at T634 by CDK1/2 negatively regulates its HIV-1 restriction in differentiated cells, but does not affect its MLV restriction in dividing cells.
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.
authors.forename: Corine
authors.initials: C
authors.lastname: St Gelais
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: de Silva
authors.affiliation: ProSci, Inc., 12170 Flint Place, Poway, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: ProSci, Inc., 12170 Flint Place, Poway, CA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Geng
authors.affiliation: Department of Pediatrics, Center for Drug Discovery, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Shepard
authors.affiliation: Department of Pediatrics, Center for Drug Discovery, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA, USA.
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA; Department of Microbial Infection and Immunity, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Yount
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA; Center for Microbial Interface Biology, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA; Department of Microbial Infection and Immunity, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA. Electronic address: wu.840@osu.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
mesh_terms: D016475:3T3 Cells; D000818:Animals; D016203:CDC2 Protein Kinase; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D057809:HEK293 Cells; D015658:HIV Infections / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000472:pathogenicity*; D007942:Leukemia, Experimental / Q000473:pathology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D012192:Retroviridae Infections / Q000473:pathology; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014162:Transfection; D014412:Tumor Virus Infections / Q000473:pathology; D020298:U937 Cells; D014779:Virus Replication / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484281:Samhd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins
keywords: HIV-1; Infection; MLV; Mouse and human SAMHD1; Phosphorylation; Restriction