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PLoS Pathog. 2019 Jan 25;15(1):e1007489. doi: 10.1371/journal.ppat.1007489. eCollection 2019 Jan.

LANA oligomeric architecture is essential for KSHV nuclear body formation and viral genome maintenance during latency.

Author information

1
Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
2
Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, United States of America.
3
Department of Virology, Institute Virology, Freie Universitat Berlin, Berlin, Germany.
4
Department of Biochemistry, School of Dentistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
5
Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Abstract

The molecular basis for the formation of functional, higher-ordered macro-molecular domains is not completely known. The Kaposi's Sarcoma-Associated Herpesvirus (KSHV) genome forms a super-molecular domain structure during latent infection that is strictly dependent on the DNA binding of the viral nuclear antigen LANA to the viral terminal repeats (TR). LANA is known to form oligomeric structures that have been implicated in viral episome maintenance. In this study, we show that the LANA oligomerization interface is required for the formation of higher-order nuclear bodies that partially colocalize with DAXX, EZH2, H3K27me3, and ORC2 but not with PML. These nuclear bodies assemble at the periphery of condensed cellular chromosomes during mitotic cell division. We demonstrate that the LANA oligomerization interface contributes to the cooperative DNA binding at the viral TR and the recruitment of ORC to the viral episome. Oligomerization mutants failed to auto-regulate LANA/ORF73 transcription, and this correlated with the loss of a chromosome conformational DNA-loop between the TR and LANA promoter. Viral genomes with LANA oligomerization mutants were subject to genome rearrangements including the loss of subgenomic DNA. Our data suggests that LANA oligomerization drives stable binding to the TR and formation of an epigenetically stable chromatin architecture resulting in higher-order LANA nuclear bodies important for viral genome integrity and long-term episome persistence.

PMID:
30682185
PMCID:
PMC6364946
DOI:
10.1371/journal.ppat.1007489
[Indexed for MEDLINE]
Free PMC Article

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