Journal Article

Transportin-1 binds to the HIV-1 capsid via a nuclear localization signal and triggers uncoating

Fernandez, Juliette, Muriaux, Delphine, Garcia, Camille, Portilho, Débora M., Gärtner, Kathleen, Henriquet, Corinne, Machado, Anthony K., Léger, Thibaut, Arhel, Nathalie J., Chamontin, Célia, Chaloin, Laurent, Yamauchi, Yohei, Blaise, Mickaël, Lyonnais, Sébastien, Pugnière, Martine, Nisole, Sébastien

2019

Overview

The initial steps of HIV replication in host cells prime the virus for passage through the nuclear pore and drive the establishment of a productive and irreparable infection 1 , 2 . The timely release of the viral genome from the capsid—referred to as uncoating—is emerging as a critical parameter for nuclear import, but the triggers and mechanisms that orchestrate these steps are unknown. Here, we identify β-karyopherin Transportin-1 (TRN-1) as a cellular co-factor of HIV-1 infection, which binds to incoming capsids, triggers their uncoating and promotes viral nuclear import. Depletion of TRN-1, which we characterized by mass spectrometry, significantly reduced the early steps of HIV-1 infection in target cells, including primary CD4+ T cells. TRN-1 bound directly to capsid nanotubes and induced dramatic structural damage, indicating that TRN-1 is necessary and sufficient for uncoating in vitro. Glycine 89 on the capsid protein, which is positioned within a nuclear localization signal in the cyclophilin A-binding loop, is critical for engaging the hydrophobic pocket of TRN-1 at position W730. In addition, TRN-1 promotes the efficient nuclear import of both viral DNA and capsid protein. Our study suggests that TRN-1 mediates the timely release of the HIV-1 genome from the capsid protein shell and efficient viral nuclear import. The host protein Transportin-1 is a co-factor of HIV-1 infection, binding to the viral capsid to regulate the release of the viral genome and promoting its nuclear import.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 13/31 / 13/89 / 14/19 / 14/28 / 14/63 / 42/44 / 631/326/421 / 631/326/596/2557 / 631/80/389/2023/2022 / 96/21 / 96/47 / Active Transport, Cell Nucleus / beta Karyopherins - chemistry / beta Karyopherins - genetics / beta Karyopherins - metabolism / Binding Sites / Biomedical and Life Sciences / Capsid - chemistry / Capsid - metabolism / Capsid protein / Capsid Proteins - chemistry / Capsid Proteins - metabolism / Capsids / CD4 antigen / CD4-Positive T-Lymphocytes - metabolism / Gene Deletion / Genomes / HEK293 Cells / HeLa Cells / HIV / HIV Infections - genetics / HIV Infections - metabolism / HIV Infections - virology / HIV-1 - metabolism / HIV-1 - physiology / Human immunodeficiency virus / Humans / Hydrophobicity / Infectious Diseases / Letter / Life Sciences / Localization / Lymphocytes T / Mass Spectrometry / Mass spectroscopy / Medical Microbiology / Microbiology / Microbiology and Parasitology / Models, Molecular / Nanotubes / Nuclear Localization Signals / Nuclear transport / Parasitology / Protein Binding / Protein Conformation / Proteins / RNA, Viral - metabolism / Uncoating / Virology / Virus Uncoating