Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency
Nelson, Jay A
AffiliationUniv Arizona, BIO5 Inst
Univ Arizona, Dept Immunobiol
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationBuehler J, Carpenter E, Zeltzer S, Igarashi S, Rak M, Mikell I, et al. (2019) Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency. PLoS Pathog 15(11): e1008037. https://doi.org/10.1371/ journal.ppat.1008037
RightsCopyright © 2019 Buehler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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AbstractSustained phosphotinositide3-kinase (PI3K) signaling is critical to the maintenance of alpha and beta herpesvirus latency. We have previously shown that the beta-herpesvirus, human cytomegalovirus (CMV), regulates epidermal growth factor receptor (EGFR), upstream of PI3K, to control states of latency and reactivation. How signaling downstream of EGFR is regulated and how this impacts CMV infection and latency is not fully understood. We demonstrate that CMV downregulates EGFR early in the productive infection, which blunts the activation of EGFR and its downstream pathways in response to stimuli. However, CMV infection sustains basal levels of EGFR and downstream pathway activity in the context of latency in CD34+ hematopoietic progenitor cells (HPCs). Inhibition of MEK/ERK, STAT or PI3K/AKT pathways downstream of EGFR increases viral reactivation from latently infected CD34(+) HPCs, defining a role for these pathways in latency. We hypothesized that CMV modulation of EGFR signaling might impact viral transcription important to latency. Indeed, EGF-stimulation increased expression of the UL138 latency gene, but not immediate early or early viral genes, suggesting that EGFR signaling promotes latent gene expression. The early growth response-1 (EGR1) transcription factor is induced downstream of EGFR signaling through the MEK/ERK pathway and is important for the maintenance of hematopoietic stemness. We demonstrate that EGR1 binds the viral genome upstream of UL138 and is sufficient to promote UL138 expression. Further, disruption of EGR1 binding upstream of UL138 prevents the establishment of latency in CD34(+) HPCs. Our results indicate a model whereby UL138 modulation of EGFR signaling feeds back to promote UL138 gene expression and suppression of replication for latency. By this mechanism, the virus has hardwired itself into host cell biology to sense and respond to changes in homeostatic host cell signaling.
NoteOpen access journal
VersionFinal published version
SponsorsNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 AI21640, P01 AI127335, R01 AI079059]; National Cancer Institute institutional T32 training grant [T32CA009213-36]; American Cancer Society Post-Doctoral Research Fellowship [129842-PF-16-212-01-TBE]
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