Transfer of the Amino-Terminal Nuclear Envelope Targeting Domain of Human MX2 Converts MX1 into an HIV-1 Resistance Factor

Caroline Goujon*, Olivier Moncorge, Helene Bauby, Tomas Doyle, Wendy S. Barclay, Michael H. Malim

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)

Abstract

The myxovirus resistance 2 (MX2) protein of humans has been identified recently as an interferon (IFN)-inducible inhibitor of human immunodeficiency virus type 1 (HIV-1) that acts at a late postentry step of infection to prevent the nuclear accumulation of viral cDNA (C. Goujon et al., Nature 502:559-562, 2013, http://dx.doi.org/10.1038/nature12542; M. Kane et al., Nature 502: 563-566, 2013, http://dx.doi.org/10.1038/nature12653; Z. Liu et al., Cell Host Microbe 14:398-410, 2013, http://dx.doi.org/10.1016/j.chom.2013.08.015). In contrast, the closely related human MX1 protein, which suppresses infection by a range of RNA and DNA viruses (such as influenza A virus [FluAV]), is ineffective against HIV-1. Using a panel of engineered chimeric MX1/2 proteins, we demonstrate that the amino-terminal 91-amino-acid domain of MX2 confers full anti-HIV-1 function when transferred to the amino terminus of MX1, and that this fusion protein retains full anti-FluAV activity. Confocal microscopy experiments further show that this MX1/2 fusion, similar to MX2 but not MX1, can localize to the nuclear envelope (NE), linking HIV-1 inhibition with MX accumulation at the NE. MX proteins are dynamin-like GTPases, and while MX1 antiviral function requires GTPase activity, neither MX2 nor MX1/2 chimeras require this attribute to inhibit HIV-1. This key discrepancy between the characteristics of MX1- and MX2-mediated viral resistance, together with previous observations showing that the L4 loop of the stalk domain of MX1 is a critical determinant of viral substrate specificity, presumably reflect fundamental differences in the mechanisms of antiviral suppression. Accordingly, we propose that further comparative studies of MX proteins will help illuminate the molecular basis and subcellular localization requirements for implementing the noted diversity of virus inhibition by MX proteins.

Original languageEnglish
Pages (from-to)9017-9026
Number of pages10
JournalJournal of Virology
Volume88
Issue number16
DOIs
Publication statusPublished - Aug 2014

Keywords

  • IMMUNODEFICIENCY-VIRUS TYPE-1
  • INFLUENZA-A VIRUS
  • VESICULAR STOMATITIS-VIRUS
  • PRIMARY HUMAN MACROPHAGES
  • INTERFERON-ALPHA
  • ANTIVIRAL ACTIVITY
  • HUMAN-CELLS
  • PROTEIN
  • INFECTION
  • GTPASE

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