title: Cyclin L2 is a critical HIV dependency factor in macrophages that controls SAMHD1 abundance.
abstract: The restriction factor SAMHD1 limits HIV-1 replication in noncycling cells. SIV and HIV-2 overcome this restriction via the accessory protein Vpx, which targets SAMHD1 for degradation through interactions with the host ubiquitin ligase adaptor DCAF1. However, the factors used by HIV-1 to replicate in macrophages, despite the presence of the restriction factor SAMHD1, are unknown. Using a yeast two-hybrid screen, we identified cyclin L2 as a DCAF1-interacting protein required for HIV-1 replication in macrophages. Knockdown of cyclin L2 results in severe attenuation of HIV-1 replication in macrophages but not cycling cells, and this effect is lost in the absence of SAMHD1. Cyclin L2 and SAMHD1 form a molecular complex that is partially dependent on the presence of DCAF1 and results in SAMHD1 degradation in a proteasome- and DCAF1-dependent manner. Therefore, cyclin L2-mediated control of SAMHD1 levels in macrophages supports HIV-1 replication.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: George Boateng
authors.initials: GB
authors.lastname: Kyei
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Ramani
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: lratner@dom.wustl.edu.
authors.forename: Lee
authors.initials: L
authors.lastname: Ratner
mesh_terms: D002478:Cells, Cultured; D016213:Cyclins / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014157:Transcription Factors / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014779:Virus Replication
chemical_list: C483080:CCNL2 protein, human; D016213:Cyclins; D014157:Transcription Factors; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins