Evolutionarily conserved pressure for the existence of distinct g2/m cell cycle arrest and a3h inactivation functions in hiv-1 vif

Ke Zhao, Juan Du, Yajuan Rui, Wenwen Zheng, Jian Kang, Jingwei Hou, Kang Wang, Wenyan Zhang, Viviana A. Simon, Xiao Fang Yu

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

HIV-1 Vif assembles the Cul5-EloB/C E3 ubiquitin ligase to induce proteasomal degradation of the cellular antiviral APOBEC3 proteins. Detailed structural studies have confirmed critical functional domains in Vif that we have previously identified as important for the interaction of EloB/C, Cul5, and CBFb. However, the mechanism by which Vif recognizes substrates remains poorly understood. Specific regions of Vif have been identified as being responsible for binding and depleting APOBEC3G and APOBEC3F. Interestingly, we have now identified distinct yet overlapping domains that are required for HIV-1 Vif-mediated G2/M-phase cell cycle arrest and APOBEC3H degradation, but not for the inactivation of APOBEC3G or APOBEC3F. Surprisingly, Vif molecules from primary HIV-1 variants that caused G2/M arrest were unable to inactivate APOBEC3H; on the other hand, HIV-1 Vif variants that could inactivate APOBEC3H were unable to induce G2/M arrest. All of these Vif variants still maintained the ability to inactivate APOBEC3G/F. Thus, primary HIV-1 variants have evolved to possess distinct functional activities that allow them to suppress APOBEC3H or cause G2 cell cycle arrest, using mutually exclusive interface domains. APOBEC3H depletion and G2 arrest are apparently evolutionary selected features that cannot co-exist on a single Vif molecule. The existence and persistence of both types of HIV-1 Vif variant suggests the importance of APOBEC3H suppression and cell cycle regulation for HIV-1’s survival in vivo.

Original languageEnglish
Pages (from-to)838-847
Number of pages10
JournalCell Cycle
Volume14
Issue number6
DOIs
StatePublished - 15 Mar 2015

Keywords

  • Apobec3h
  • Cell cycle regulation
  • Evolutionary selection
  • Proteasomal degradation
  • Vif

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