The nucleic acid binding protein SFPQ represses EBV lytic reactivation by promoting histone H1 expression

Laura A. Murray-Nerger, Clarisel Lozano, Eric M. Burton, Yifei Liao, Nathan A. Ungerleider, Rui Guo and Benjamin E. Gewurz ()
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Laura A. Murray-Nerger: Brigham and Women’s Hospital
Clarisel Lozano: Brigham and Women’s Hospital
Eric M. Burton: Brigham and Women’s Hospital
Yifei Liao: Brigham and Women’s Hospital
Nathan A. Ungerleider: Tulane University
Rui Guo: Tufts University
Benjamin E. Gewurz: Brigham and Women’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Epstein-Barr virus (EBV) uses a biphasic lifecycle of latency and lytic reactivation to infect >95% of adults worldwide. Despite its central role in EBV persistence and oncogenesis, much remains unknown about how EBV latency is maintained. We used a human genome-wide CRISPR/Cas9 screen to identify that the nuclear protein SFPQ was critical for latency. SFPQ supported expression of linker histone H1, which stabilizes nucleosomes and regulates nuclear architecture, but has not been previously implicated in EBV gene regulation. H1 occupied latent EBV genomes, including the immediate early gene BZLF1 promoter. Upon reactivation, SFPQ was sequestered into sub-nuclear puncta, and EBV genomic H1 occupancy diminished. Enforced H1 expression blocked EBV reactivation upon SFPQ knockout, confirming it as necessary downstream of SFPQ. SFPQ knockout triggered reactivation of EBV in B and epithelial cells, as well as of Kaposi’s sarcoma-associated herpesvirus in B cells, suggesting a conserved gamma-herpesvirus role. These findings highlight SFPQ as a major regulator of H1 expression and EBV latency.

Date: 2024
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DOI: 10.1038/s41467-024-48333-x

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