Vpr Targets TET2 for Degradation by CRL4 VprBP E3 Ligase to Sustain IL-6 Expression and Enhance HIV-1 Replication

Lei Lv, Qi Wang, Yanping Xu, Li Chung Tsao, Tadashi Nakagawa, Haitao Guo, Lishan Su, Yue Xiong

研究成果: Article

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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. HIV-1 Vpr protein counteracts host anti-viral restriction factors to facilitate viral replication and disease progression. Lv et al. demonstrate that Vpr promotes degradation of TET DNA dioxygenases. TET2 deletion or depletion enhances HIV-1 replication and sustains pro-inflammatory cytokine IL-6, while blocking IL-6 reduces Vpr's ability to enhance HIV-1 replication.

元の言語English
ページ(範囲)961-970.e5
ジャーナルMolecular Cell
70
発行部数5
DOI
出版物ステータスPublished - 2018 6 7

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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