ZIC2 is essential for maintenance of latency and is a target of an immediate early protein during Kaposi's sarcoma-associated herpesvirus lytic reactivation

Yuanzhi Lyu, Kazushi Nakano, Ryan R. Davis, Clifford G Tepper, Mel Campbell, Yoshihiro Izumiya

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Bivalent histone modifications are defined as repressive and activating epigenetic marks that simultaneously decorate the same genomic region. The H3K27me3 mark silences gene expression, while the H3K4me3 mark prevents the region from becoming permanently silenced and prepares the domain for activation when needed. Specific regions of Kaposi's sarcoma-associated herpesvirus (KSHV) latent episomes are poised to be activated by the KSHV replication and transcription activator (K-Rta). How KSHV episomes are prepared such that they maintain latent infection and switch to lytic replication by K-Rta remains unclear. K-Rta transactivation activity requires a protein degradation function; thus, we hypothesized that identification of cellular substrates of K-Rta may provide insight into the maintenance of KSHV latent infection and the switch to lytic replication. Here we show that a zinc finger protein, ZIC2, a key regulator for central nervous system development, is a substrate of K-Rta and is responsible for maintaining latency. K-Rta directly interacted with ZIC2 and functioned as an E3 ligase to ubiquitinate ZIC2. ZIC2 localized at immediate early and early gene cluster regions of the KSHV genome and contributed to tethering of polycomb repressive complex 2 through physical interaction, thus maintaining H3K27me3 marks at the K-Rta promoter. Accordingly, depletion of ZIC2 shifted the balance of bivalent histone modifications toward more active forms and induced KSHV reactivation in naturally infected cells. We suggest that ZIC2 turnover by K-Rta is a strategy employed by KSHV to favor the transition from latency to lytic replication.

Original languageEnglish (US)
Article numbere00980-17
JournalJournal of Virology
Volume91
Issue number21
DOIs
StatePublished - Nov 1 2017

Keywords

  • Epigenetic
  • Kaposi's sarcoma-associated herpesvirus
  • PRC2
  • Reactivation
  • Transcriptional regulation
  • ZIC2

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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