MORC2 restriction factor silences HIV proviral expression

Lasserre, A.; Marie, S.; Morel, M.; Martin, M. M.; Legrand, A.; Vauthier, V.; Cimarelli, A.; Etienne, L.; Margottin-Goguet, F.; Matkovic, R.

doi:10.1101/2023.03.29.534756

bioRxiv · 10.1101/2023.03.29.534756

MORC2 restriction factor silences HIV proviral expression

Lasserre, A.·Marie, S.·Morel, M.·Martin, M. M.·Legrand, A.·Vauthier, V.·Cimarelli, A.·Etienne, L.·Margottin-Goguet, F.·Matkovic, R.

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Abstract

The HUSH complex (composed of TASOR, MPP8 and periphilin) represses HIV-1 expression by inducing both propagation of repressive epigenetic marks and degradation of the nascent transcript. Vpx from HIV-2, and Vpr proteins from some simian lentiviruses (SIVs), antagonize HUSH, thereby increasing proviral expression. The chromatin-remodeler MORC2 protein plays a critical role in the epigenetic silencing of host genes by HUSH. Here, we deciphered the role of MORC2 in HIV-1 silencing. We show that MORC2, in contrast to HUSH components, presents strong signatures of positive selection during primate evolution. However, while HUSH is degraded upon HIV-2 infection in a Vpx-dependent manner, MORC2 levels are rather increased, due to the loss of the HUSH-mediated repression. Our results suggest that lentiviral proteins from the Vpr/Vpx family have not driven primate MORC2 evolution. Our findings indicate that MORC2 negatively regulates HIV-1 provirus expression. Mechanistically, we show that MORC2 is recruited to the integrated HIV-1 provirus locus and is required for TASOR-mediated post-transcriptional HIV-1 silencing suggesting that MORC2 sets the stage for the HUSH-mediated HIV-1 nascent RNA degradation. We demonstrate that reducing MORC2 levels diminishes provirus silencing in both monoclonal and polyclonal cellular models of HIV-1 latency. These results suggest that MORC2 has evolved adaptations during primate diversification, possibly in response to challenges posed by DNA pathogens or retroelement integration into the host genome.

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Lasserre, A., Marie, S., Morel, M., Martin, M. M., Legrand, A., Vauthier, V., Cimarelli, A., Etienne, L., Margottin-Goguet, F., Matkovic, R.. 2023-03-29. MORC2 restriction factor silences HIV proviral expression. https://doi.org/10.1101/2023.03.29.534756

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