Multiple components of the nuclear pore complex and nuclear import machinery enable a protein called human myxovirus resistance 2 (MX2) to inhibit HIV-1 infection, according to a study published in the open-access journal PLOS Pathogens.
In eukaryotic cells, a membrane barrier called the nuclear envelope separates the nucleus from the cytoplasm. The movement of large molecules through the nuclear envelope and into the cell nucleus is regulated by large protein structures called nuclear pore complexes.
To infect cells productively, HIV-1 must traverse the nuclear envelope to enable integration of the viral DNA into the genomic DNA of host cells. MX2, which is localized at the cytoplasmic face of the nuclear envelope, inhibits infection by blocking the nuclear import of HIV-1 DNA and preventing its accumulation within the nucleus. However, the precise mechanism of viral inhibition has not been clear.
In the new study, researchers show that MX2 interacts with multiple protein components of the nuclear pore complex, as well as the nuclear transport receptor transportin-1 - a component of the nuclear import pathway. In yeast two-hybrid screen five out of seven primary candidate interactors were nucleoporins or nucleoporin-like proteins, though none of these candidates were identified when screening with a mutant RRR11-13A N-MX2 fragment. Interactions were confirmed by co-immunoprecipitation, and RNA silencing experiments in cell lines and primary CD4+ T cells demonstrated that multiple components of the nuclear pore complex and nuclear import machinery can impact MX2 anti-viral activity. In particular, the phenylalanine-glycine (FG) repeat containing cytoplasmic filament nucleoporin NUP214, and transport receptor transportin-1 (TNPO1) were consistently required for full MX2, and interferon-mediated, anti-viral function.
Both proteins were shown to interact with the triple arginine motif, and confocal fluorescence microscopy revealed that their simultaneous depletion resulted in diminished MX2 accumulation at the nuclear envelope. The findings suggest that TNPO1 and nucleoporins (particularly NUP214) help position MX2 at the nuclear envelope to promote MX2-mediated restriction of HIV-1.
According to the authors, these new insights could lead to the development of more effective therapies for HIV-infected patients.
How HIV DNA is blocked from entering the cell nucleus
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