Vpr Targets TET2 for Degradation by CRL4VprBP E3 Ligase to Sustain IL-6 Expression and Enhance HIV-1 Replication

Mol Cell. 2018 Jun 7;70(5):961-970.e5. doi: 10.1016/j.molcel.2018.05.007. Epub 2018 Jun 7.

Abstract

HIV-1 expresses several accessory proteins to counteract host anti-viral restriction factors to facilitate viral replication and disease progression. One such protein, Vpr, has been implicated in affecting multiple cellular processes, but its mechanism remains elusive. Here we report that Vpr targets TET2 for polyubiquitylation by the VprBP-DDB1-CUL4-ROC1 E3 ligase and subsequent degradation. Genetic inactivation or Vpr-mediated degradation of TET2 enhances HIV-1 replication and substantially sustains expression of the pro-inflammatory cytokine interleukin-6 (IL-6). This process correlates with reduced recruitment of histone deacetylase 1 and 2 to the IL-6 promoter, thus enhancing its histone H3 acetylation level during resolution phase. Blocking IL-6 signaling reduced the ability of Vpr to enhance HIV-1 replication. We conclude that HIV-1 Vpr degrades TET2 to sustain IL-6 expression to enhance viral replication and disease progression. These results suggest that disrupting the Vpr-TET2-IL6 axis may prove clinically beneficial to reduce both viral replication and inflammation during HIV-1 infection.

Keywords: HIV-1; IL-6; TET2; Vpr; VprBP; inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • HEK293 Cells
  • HIV-1 / genetics
  • HIV-1 / growth & development
  • HIV-1 / metabolism*
  • HIV-1 / pathogenicity
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / metabolism
  • Host-Pathogen Interactions
  • Humans
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Jurkat Cells
  • Monocytes / enzymology
  • Monocytes / virology*
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases
  • Proteolysis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction
  • THP-1 Cells
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Virus Replication*
  • vpr Gene Products, Human Immunodeficiency Virus / genetics
  • vpr Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-6
  • Proto-Oncogene Proteins
  • vpr Gene Products, Human Immunodeficiency Virus
  • vpr protein, Human immunodeficiency virus 1
  • Dioxygenases
  • TET2 protein, human
  • Ubiquitin-Protein Ligases
  • DCAF1 protein, human
  • Protein Serine-Threonine Kinases
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2