Open AccessLANA oligomeric architecture is essential for KSHV nuclear body formation and viral genome maintenance during latency
Author(s) -
Alessandra De Leo,
Zhong Deng,
Olga Vladimirova,
Horng-Shen Chen,
Jayaraju Dheekollu,
Abram Calderon,
Kenneth A. Myers,
James Hayden,
Frederick Keeney,
Benedikt B. Kaufer,
Yan Yuan,
Erle S. Robertson,
Paul M. Lieberman
Publication year - 2019
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1007489
Subject(s) - biology , kaposi's sarcoma associated herpesvirus , chromatin , subgenomic mrna , genome , microbiology and biotechnology , death associated protein 6 , dna , dna replication , dna binding domain , transcription (linguistics) , genetics , nuclear protein , transcription factor , gene , virus , viral disease , herpesviridae , linguistics , philosophy
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.