Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2

  1. Melissa Kane
  2. Stephanie V Rebensburg
  3. Matthew A Takata
  4. Trinity M Zang
  5. Masahiro Yamashita
  6. Mamuka Kvaratskhelia
  7. Paul D Bieniasz  Is a corresponding author
  1. Rockefeller University, United States
  2. University of Colorado Denver, United States
  3. Aaron Diamond AIDS Research Center, United States

Abstract

HIV-1 accesses the nuclear DNA of interphase cells via a poorly defined process involving functional interactions between the capsid protein (CA) and nucleoporins (Nups). Here, we show that HIV-1 CA can bind multiple Nups, and that both natural and manipulated variation in Nup levels impacts HIV-1 infection in a manner that is strikingly dependent on cell-type, cell-cycle, and cyclophilin A (CypA). We also show that Nups mediate the function of the antiviral protein MX2, and that MX2 can variably inhibit non-viral NLS function. Remarkably, both enhancing and inhibiting effects of cyclophilin A and MX2 on various HIV-1 CA mutants could be induced or abolished by manipulating levels of the Nup93 subcomplex, the Nup62 subcomplex, NUP88, NUP21, RANBP2, or NUP153. Our findings suggest that several Nup-dependent 'pathways' are variably exploited by HIV-1 to target host DNA in a cell-type, cell-cycle, CypA and CA-sequence dependent manner, and are differentially inhibited by MX2.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Melissa Kane

    Laboratory of Retrovirology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Stephanie V Rebensburg

    Division of Infectious Diseases, University of Colorado Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew A Takata

    Laboratory of Retrovirology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Trinity M Zang

    Laboratory of Retrovirology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Masahiro Yamashita

    Aaron Diamond AIDS Research Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Mamuka Kvaratskhelia

    Division of Infectious Diseases, University of Colorado Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Paul D Bieniasz

    Laboratory of Retrovirology, Rockefeller University, New York, United States
    For correspondence
    pbieniasz@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2368-3719

Funding

Howard Hughes Medical Institute (Investigator Award)

  • Paul D Bieniasz

National Institute of Allergy and Infectious Diseases (R3764003)

  • Paul D Bieniasz

National Institute of Allergy and Infectious Diseases (R01AI100720)

  • Masahiro Yamashita

National Institute of Allergy and Infectious Diseases (R01AI062520)

  • Mamuka Kvaratskhelia

National Institute of Allergy and Infectious Diseases (F32AI116263)

  • Melissa Kane

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2018, Kane et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,989
    views
  • 795
    downloads
  • 117
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Melissa Kane
  2. Stephanie V Rebensburg
  3. Matthew A Takata
  4. Trinity M Zang
  5. Masahiro Yamashita
  6. Mamuka Kvaratskhelia
  7. Paul D Bieniasz
(2018)
Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2
eLife 7:e35738.
https://doi.org/10.7554/eLife.35738

Share this article

https://doi.org/10.7554/eLife.35738

Further reading

    1. Cell Biology
    Giuliana Giamundo, Daniela Intartaglia ... Ivan Conte
    Research Article

    Endosomes have emerged as major signaling hubs where different internalized ligand–receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane–actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.

    1. Cell Biology
    Marjan Slak Rupnik
    Insight

    Functional subpopulations of β-cells emerge to control pulsative insulin secretion in the pancreatic islets of mice through calcium oscillations.