title: The Vpx lentiviral accessory protein targets SAMHD1 for degradation in the nucleus.
abstract: Sterile alpha motif domain- and HD domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphohydrolase that restricts the replication of lentiviruses in myeloid cells by hydrolyzing the cellular deoxynucleotide triphosphates to a level below that which is required for reverse transcription. Human immunodeficiency virus type 2 (HIV-2) and some simian immunodeficiency viruses (SIVs) encode the accessory protein viral protein X (Vpx) that counteracts SAMHD1. Vpx recruits SAMHD1 to a cullin4A-RING E3 ubiquitin ligase (CRL4), which targets the enzyme for proteasomal degradation. Vpx and SAMHD1 both localize to the nucleus of the cell. We identified the nuclear localization sequence (NLS) of SAMHD1 as a conserved KRPR sequence at amino acid residues 11 to 14. SAMHD1 lacking a functional NLS localized to the cytoplasm but retained its triphosphohydrolase and antiviral activities. However, cytoplasmic SAMHD1 was resistant to Vpx-induced degradation, and its antiviral activity was not counteracted by Vpx. Cytoplasmic SAMHD1 interacted with Vpx and retained it in the cytoplasm. The inhibition of nuclear export with leptomycin B did not impair the ability of Vpx to degrade SAMHD1. These findings suggest that SAMHD1 is targeted by Vpx for ubiquitination and degradation in the nucleus.
authors.affiliation: Microbiology Department, New York University School of Medicine, New York, New York, USA.
authors.forename: Henning
authors.initials: H
authors.lastname: Hofmann
authors.forename: Eric C
authors.initials: EC
authors.lastname: Logue
authors.forename: Nicolin
authors.initials: N
authors.lastname: Bloch
authors.forename: Waaqo
authors.initials: W
authors.lastname: Daddacha
authors.forename: Sylvie B
authors.initials: SB
authors.lastname: Polsky
authors.forename: Megan L
authors.initials: ML
authors.lastname: Schultz
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Landau
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D059748:Proteolysis; D000076106:SAM Domain and HD Domain-Containing Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; D019913:Nuclear Localization Signals; C074286:VPX protein, Human immunodeficiency virus 2; D054334:Viral Regulatory and Accessory Proteins; D044767:Ubiquitin-Protein Ligases; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins