The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr.
Cuesta, Sergio Martínez
Sarafianos, Stefan G
Cell host & microbe
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Dupont, L., Bloor, S., Williamson, J., Cuesta, S. M., Shah, R., Teixeira-Silva, A., Naamati, A., et al. (2021). The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr.. Cell host & microbe, 29 (5), 792-805.e6. https://doi.org/10.1016/j.chom.2021.03.001
Silencing of nuclear DNA is an essential feature of the innate immune response to invading pathogens. Early in lentiviral infection, unintegrated viral cDNA accumulates in the nucleus, yet remains poorly expressed. In HIV-1-like lentiviruses, the Vpr accessory protein enhances unintegrated viral DNA expression, suggesting Vpr antagonises cellular restriction. We previously showed how Vpr remodels the host proteome, identifying multiple cellular targets. We now screen these using a targeted CRISPR-Cas9 library, identifying SMC5-SMC6 complex localization factor 2 (SLF2) as the Vpr target responsible for silencing unintegrated HIV-1. SLF2 recruits the SMC5/6 complex to unintegrated lentiviruses, and depletion of SLF2, or the SMC5/6 complex, increases viral expression. Using ATAC-seq, we show that Vpr-mediated SLF2 depletion increases chromatin accessibility of unintegrated virus, suggesting the SMC5/6 complex compacts viral chromatin to silence gene expression. This work implicates the SMC5/6 complex in nuclear immunosurveillance of extrachromosomal DNA and defines an evolutionarily conserved antagonism by Vpr.
Wellcome Trust (210688/Z/18/Z)
WELLCOME TRUST (109074/Z/15/Z)
Wellcome Trust (209441/Z/17/Z)
Addenbrooke's Charitable Trust (ACT) (Minute 42/18 C3)
External DOI: https://doi.org/10.1016/j.chom.2021.03.001
This record's URL: https://www.repository.cam.ac.uk/handle/1810/319874
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/