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Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency

Sustained 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 latenc...

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Autores principales: Buehler, Jason, Carpenter, Ethan, Zeltzer, Sebastian, Igarashi, Suzu, Rak, Michael, Mikell, Iliyana, Nelson, Jay A., Goodrum, Felicia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855412/
https://www.ncbi.nlm.nih.gov/pubmed/31725811
http://dx.doi.org/10.1371/journal.ppat.1008037
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author Buehler, Jason
Carpenter, Ethan
Zeltzer, Sebastian
Igarashi, Suzu
Rak, Michael
Mikell, Iliyana
Nelson, Jay A.
Goodrum, Felicia
author_facet Buehler, Jason
Carpenter, Ethan
Zeltzer, Sebastian
Igarashi, Suzu
Rak, Michael
Mikell, Iliyana
Nelson, Jay A.
Goodrum, Felicia
author_sort Buehler, Jason
collection PubMed
description Sustained 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.
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spelling pubmed-68554122019-11-22 Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency Buehler, Jason Carpenter, Ethan Zeltzer, Sebastian Igarashi, Suzu Rak, Michael Mikell, Iliyana Nelson, Jay A. Goodrum, Felicia PLoS Pathog Research Article Sustained 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. Public Library of Science 2019-11-14 /pmc/articles/PMC6855412/ /pubmed/31725811 http://dx.doi.org/10.1371/journal.ppat.1008037 Text en © 2019 Buehler et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Buehler, Jason
Carpenter, Ethan
Zeltzer, Sebastian
Igarashi, Suzu
Rak, Michael
Mikell, Iliyana
Nelson, Jay A.
Goodrum, Felicia
Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency
title Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency
title_full Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency
title_fullStr Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency
title_full_unstemmed Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency
title_short Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency
title_sort host signaling and egr1 transcriptional control of human cytomegalovirus replication and latency
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855412/
https://www.ncbi.nlm.nih.gov/pubmed/31725811
http://dx.doi.org/10.1371/journal.ppat.1008037
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