title: The HIV-1 protein Vpr targets the endoribonuclease Dicer for proteasomal degradation to boost macrophage infection.
abstract: The HIV-1 protein Vpr enhances macrophage infection, triggers G2 cell cycle arrest, and targets cells for NK-cell killing. Vpr acts through the CRL4(DCAF1) ubiquitin ligase complex to cause G2 arrest and trigger expression of NK ligands. Corresponding ubiquitination targets have not been identified. UNG2 and SMUG1 are the only known substrates for Vpr-directed depletion through CRL4(DCAF1). Here we identify the endoribonuclease Dicer as a target of HIV-1 Vpr-directed proteasomal degradation through CRL4(DCAF1). We show that HIV-1 Vpr inhibits short hairpin RNA function as expected upon reduction of Dicer levels. Dicer inhibits HIV-1 replication in T cells. We demonstrate that Dicer also restricts HIV-1 replication in human monocyte-derived macrophages (MDM) and that reducing Dicer expression in MDMs enhances HIV-1 infection in a Vpr-dependent manner. Our results support a model in which Vpr complexes with human Dicer to boost its interaction with the CRL4(DCAF1) ubiquitin ligase complex and its subsequent degradation.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Laurieann
authors.initials: L
authors.lastname: Casey Klockow
authors.forename: Hamayun J
authors.initials: HJ
authors.lastname: Sharifi
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wen
authors.forename: Meg
authors.initials: M
authors.lastname: Flagg
authors.forename: Andrea K M
authors.initials: AK
authors.lastname: Furuya
authors.forename: Michael
authors.initials: M
authors.lastname: Nekorchuk
authors.forename: Carlos M C
authors.initials: CM
authors.lastname: de Noronha
mesh_terms: D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D043244:Ribonuclease III / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; C408087:DICER1 protein, human; D043244:Ribonuclease III; D046988:Proteasome Endopeptidase Complex; D053487:DEAD-box RNA Helicases
keywords: CRL4; Cullin4; DCAF1; Dicer; HIV-1; Suppressor of silencing (SRS); Ubiquitin ligase; Vpr; miRNA