Early events of the human immunodeficiency virus 1 (HIV-1) lifecycle, such as post-entry virus trafficking, uncoating and nuclear import, are poorly characterized because of limited understanding of virus–host interactions. Here, we used mass spectrometry-based proteomics to delineate cellular binding partners of curved HIV-1 capsid lattices and identified Sec24C as an HIV-1 host dependency factor. Gene deletion and complementation in Jurkat cells revealed that Sec24C facilitates infection and markedly enhances HIV-1 spreading infection. Downregulation of Sec24C in HeLa cells substantially reduced HIV-1 core stability and adversely affected reverse transcription, nuclear import and infectivity. Live-cell microscopy showed that Sec24C co-trafficked with HIV-1 cores in the cytoplasm during virus ingress. Biochemical assays demonstrated that Sec24C directly and specifically interacted with hexameric capsid lattices. A 2.3-Å resolution crystal structure of Sec24C228–242 in the complex with a capsid hexamer revealed that the Sec24C FG-motif bound to a pocket comprised of two adjoining capsid subunits. Combined with previous data1–4, our findings indicate that a capsid-binding FG-motif is conserved in unrelated proteins present in the cytoplasm (Sec24C), the nuclear pore (Nup153; refs. 3,4) and the nucleus (CPSF6; refs. 1,2). We propose that these virus–host interactions during HIV-1 trafficking across different cellular compartments are crucial for productive infection of target cells.
CITATION STYLE
Rebensburg, S. V., Wei, G., Larue, R. C., Lindenberger, J., Francis, A. C., Annamalai, A. S., … Kvaratskhelia, M. (2021). Sec24C is an HIV-1 host dependency factor crucial for virus replication. Nature Microbiology, 6(4), 435–444. https://doi.org/10.1038/s41564-021-00868-1
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