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Transportin 3 Promotes a Nuclear Maturation Step Required for Efficient HIV-1 Integration

Zhou, LH; Sokolskaja, E; Jolly, C; James, W; Cowley, SA; Fassati, A; (2011) Transportin 3 Promotes a Nuclear Maturation Step Required for Efficient HIV-1 Integration. PLoS Pathogens , 7 (8) , Article e1002194. 10.1371/journal.ppat.1002194. Green open access

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Abstract

The HIV/AIDS pandemic is a major global health threat and understanding the detailed molecular mechanisms of HIV replication is critical for the development of novel therapeutics. To replicate, HIV-1 must access the nucleus of infected cells and integrate into host chromosomes, however little is known about the events occurring post-nuclear entry but before integration. Here we show that the karyopherin Transportin 3 (Tnp3) promotes HIV-1 integration in different cell types. Furthermore Tnp3 binds the viral capsid proteins and tRNAs incorporated into viral particles. Interaction between Tnp3, capsid and tRNAs is stronger in the presence of RanGTP, consistent with the possibility that Tnp3 is an export factor for these substrates. In agreement with this interpretation, we found that Tnp3 exports from the nuclei viral tRNAs in a RanGTP-dependent way. Tnp3 also binds and exports from the nuclei some species of cellular tRNAs with a defective 3'CCA end. Depletion of Tnp3 results in a re-distribution of HIV-1 capsid proteins between nucleus and cytoplasm however HIV-1 bearing the N74D mutation in capsid, which is insensitive to Tnp3 depletion, does not show nucleocytoplasmic redistribution of capsid proteins. We propose that Tnp3 promotes HIV-1 infection by displacing any capsid and tRNA that remain bound to the pre-integration complex after nuclear entry to facilitate integration. The results also provide evidence for a novel tRNA nucleocytoplasmic trafficking pathway in human cells.

Type: Article
Title: Transportin 3 Promotes a Nuclear Maturation Step Required for Efficient HIV-1 Integration
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1002194
Publisher version: http://dx.doi.org/10.1371/journal.ppat.1002194
Language: English
Additional information: © 2011 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: IMMUNODEFICIENCY-VIRUS TYPE-1, REVERSE TRANSCRIPTION COMPLEXES, TRANSFER-RNA, NONDIVIDING CELLS, SACCHAROMYCES-CEREVISIAE, PREINTEGRATION COMPLEX, QUANTITATIVE ASSAY, LENTIVIRAL VECTOR, BINDING PROTEIN, CAPSID PROTEIN
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1322097
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