FOXO transcription factors activate alternative major immediate early promoters to induce human cytomegalovirus reactivation

Andrew E. Hale, Donna Collins-Mcmillen, Erik M. Lenarcic, Suzu Igarashi, Jeremy P. Kamil, Felicia Goodrum, Nathaniel J. Moorman

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Human progenitor cells (HPCs) support human cytomegalovirus (HCMV) latency, and their differentiation along the myeloid lineage triggers cellular cues that drive reactivation. A key step during HCMV reactivation in latently infected HPCs is reexpression of viral major immediate early (MIE) genes. We recently determined that the major immediate early promoter (MIEP), which is primarily responsible for MIE gene expression during lytic replication, remains silent during reactivation. Instead, alternative promoters in theMIE locus are induced by reactivation stimuli. Here, we find that forkhead family (FOXO) transcription factors are critical for activation of alternative MIE promoters during HCMV reactivation, as mutating FOXO binding sites in alternative MIE promoters decreased HCMV IE gene expression upon reactivation and significantly decreased the production of infectious virus from latently infected primary CD34+ HPCs. These findings establish a mechanistic link by which infected cells sense environmental cues to regulate latency and reactivation, and emphasize the role of contextual activation of alternative MIE promoters as the primary drivers of reactivation.

Original languageEnglish (US)
Pages (from-to)18764-18770
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number31
DOIs
StatePublished - Aug 4 2020

Keywords

  • Foxo
  • Hcmv
  • Herpesvirus
  • Latency
  • Reactivation

ASJC Scopus subject areas

  • General

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