PRC1-independent binding and activity of RYBP on the KSHV genome during de novo infection.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes lifelong infection in humans by establishing latency after primary infection. Latent infection is a prerequisite for both persistent infection and the development of KSHV-associated cancers. While viral lytic genes are transiently expressed after primary infection, their expression is significantly restricted and concomitant with the binding of host epigenetic repressors Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2) to lytic genes. PRC1 and PRC2 mediate the repressive histone marks H2AK119ub and H3K27me3, respectively, and maintain heterochromatin structure on KSHV lytic genes to inhibit their expression. In contrast to PRC2, little is known about the recruitment and role of PRC1 factors on the KSHV genome following de novo infection. Thus, the goal of this study was to examine the function of PRC1 factors in the establishment of KSHV latency. To address this question, we performed an shRNA screen targeting 7 different components of the canonical and non-canonical PRC1 complexes during primary KSHV infection. We found that RYBP, a main subunit of the non-canonical PRC1 complexes, is a potent repressor of KSHV lytic genes that can bind to the viral genome and inhibit lytic genes as early as 4 hours post infection. Surprisingly, our ChIP analyses showed that RYBP binds to lytic viral gene promoters in a PRC1-independent manner, does not affect PRC1 activity on the KSHV genome, and can reduce the level of histone marks associated with transcription elongation. Our data also suggest that RYBP can repress the viral lytic cycle after primary infection by inhibiting the transcription elongation of the lytic cycle inducer KSHV gene RTA. Based on our results we propose that RYBP uses a PRC1-independent mechanism to block KSHV RTA expression thereby promoting the establishment of KSHV latency following de novo infection.

• Authors: See-Chi Lee, Zsolt Toth
• Journal: PLoS pathogens (PLoS Pathog) Vol. 18 Issue 8 Pg. e1010801 (08 2022) ISSN: 1553-7374 [Electronic] United States
• PMID: 36026503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Cell Cycle Proteins
• Histones
• PRC1 protein, human
• RYBP protein, human
• Repressor Proteins
• Polycomb Repressive Complex 2

Topics

• Cell Cycle Proteins (metabolism)
• Gene Expression Regulation, Viral
• Herpesviridae Infections (metabolism)
• Herpesvirus 8, Human (genetics, metabolism)
• Histones (genetics, metabolism)
• Humans
• Polycomb Repressive Complex 2 (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Virus Latency (genetics)