Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways

ABSTRACT Regulation of epidermal growth factor (EGF) receptor (EGFR) signaling is critical for the replication of human cytomegalovirus (HCMV) as well as latency and reactivation in CD34+ hematopoietic progenitor cells. HCMV microRNAs (miRNAs) provide a means to modulate the signaling activated by E...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Meaghan H. Hancock, Jennifer Mitchell, Felicia D. Goodrum, Jay A. Nelson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	GAB1 UL138 cytomegalovirus miRNA Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e2fc9318c32f4c518a32c8f411179a7e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e2fc9318c32f4c518a32c8f411179a7e
record_format	dspace
spelling	oai:doaj.org-article:e2fc9318c32f4c518a32c8f411179a7e2021-11-15T15:30:51ZHuman Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways10.1128/mSphere.00582-202379-5042https://doaj.org/article/e2fc9318c32f4c518a32c8f411179a7e2020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00582-20https://doaj.org/toc/2379-5042ABSTRACT Regulation of epidermal growth factor (EGF) receptor (EGFR) signaling is critical for the replication of human cytomegalovirus (HCMV) as well as latency and reactivation in CD34+ hematopoietic progenitor cells. HCMV microRNAs (miRNAs) provide a means to modulate the signaling activated by EGF through targeting components of the EGFR signaling pathways. Here, we demonstrate that HCMV miR-US5-2 directly downregulates the critical EGFR adaptor protein GAB1 that mediates activation and sustained signaling through the phosphatidylinositol 3-kinase (PI3K) and MEK/extracellular signal-regulated kinase (ERK) pathways and cellular proliferation in response to EGF. Expression of HCMV UL138 is regulated by the transcription factor early growth response gene 1 (EGR1) downstream of EGFR-induced MEK/ERK signaling. We show that by targeting GAB1 and attenuating MEK/ERK signaling, miR-US5-2 indirectly regulates EGR1 and UL138 expression, which implicates the miRNA in critical regulation of HCMV latency. IMPORTANCE Human cytomegalovirus (HCMV) causes significant disease in immunocompromised individuals, including transplant patients. HCMV establishes latency in hematopoietic stem cells in the bone marrow. The mechanisms governing latency and reactivation of viral replication are complex and not fully understood. HCMV-encoded miRNAs are small regulatory RNAs that reduce protein expression. In this study, we found that the HCMV miRNA miR-US5-2 targets the epidermal growth factor receptor (EGFR) adaptor protein GAB1 which directly affects downstream cellular signaling pathways activated by EGF. Consequently, miR-US5-2 blocks the EGF-mediated proliferation of human fibroblasts. Early growth response gene 1 (EGR1) is a transcription factor activated by EGFR signaling that regulates expression of HCMV UL138. We show that miR-US5-2 regulates UL138 expression through GAB1-mediated downregulation of the signaling pathways that lead to EGR1 expression. These data suggest that miR-US5-2, through downregulation of GAB1, could play a critical role during reactivation from latency by reducing proliferation and UL138 expression.Meaghan H. HancockJennifer MitchellFelicia D. GoodrumJay A. NelsonAmerican Society for MicrobiologyarticleGAB1UL138cytomegalovirusmiRNAMicrobiologyQR1-502ENmSphere, Vol 5, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	GAB1 UL138 cytomegalovirus miRNA Microbiology QR1-502
spellingShingle	GAB1 UL138 cytomegalovirus miRNA Microbiology QR1-502 Meaghan H. Hancock Jennifer Mitchell Felicia D. Goodrum Jay A. Nelson Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways
description	ABSTRACT Regulation of epidermal growth factor (EGF) receptor (EGFR) signaling is critical for the replication of human cytomegalovirus (HCMV) as well as latency and reactivation in CD34+ hematopoietic progenitor cells. HCMV microRNAs (miRNAs) provide a means to modulate the signaling activated by EGF through targeting components of the EGFR signaling pathways. Here, we demonstrate that HCMV miR-US5-2 directly downregulates the critical EGFR adaptor protein GAB1 that mediates activation and sustained signaling through the phosphatidylinositol 3-kinase (PI3K) and MEK/extracellular signal-regulated kinase (ERK) pathways and cellular proliferation in response to EGF. Expression of HCMV UL138 is regulated by the transcription factor early growth response gene 1 (EGR1) downstream of EGFR-induced MEK/ERK signaling. We show that by targeting GAB1 and attenuating MEK/ERK signaling, miR-US5-2 indirectly regulates EGR1 and UL138 expression, which implicates the miRNA in critical regulation of HCMV latency. IMPORTANCE Human cytomegalovirus (HCMV) causes significant disease in immunocompromised individuals, including transplant patients. HCMV establishes latency in hematopoietic stem cells in the bone marrow. The mechanisms governing latency and reactivation of viral replication are complex and not fully understood. HCMV-encoded miRNAs are small regulatory RNAs that reduce protein expression. In this study, we found that the HCMV miRNA miR-US5-2 targets the epidermal growth factor receptor (EGFR) adaptor protein GAB1 which directly affects downstream cellular signaling pathways activated by EGF. Consequently, miR-US5-2 blocks the EGF-mediated proliferation of human fibroblasts. Early growth response gene 1 (EGR1) is a transcription factor activated by EGFR signaling that regulates expression of HCMV UL138. We show that miR-US5-2 regulates UL138 expression through GAB1-mediated downregulation of the signaling pathways that lead to EGR1 expression. These data suggest that miR-US5-2, through downregulation of GAB1, could play a critical role during reactivation from latency by reducing proliferation and UL138 expression.
format	article
author	Meaghan H. Hancock Jennifer Mitchell Felicia D. Goodrum Jay A. Nelson
author_facet	Meaghan H. Hancock Jennifer Mitchell Felicia D. Goodrum Jay A. Nelson
author_sort	Meaghan H. Hancock
title	Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways
title_short	Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways
title_full	Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways
title_fullStr	Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways
title_full_unstemmed	Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways
title_sort	human cytomegalovirus mir-us5-2 downregulation of gab1 regulates cellular proliferation and <italic toggle="yes">ul138</italic> expression through modulation of epidermal growth factor receptor signaling pathways
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/e2fc9318c32f4c518a32c8f411179a7e
work_keys_str_mv	AT meaghanhhancock humancytomegalovirusmirus52downregulationofgab1regulatescellularproliferationanditalictoggleyesul138italicexpressionthroughmodulationofepidermalgrowthfactorreceptorsignalingpathways AT jennifermitchell humancytomegalovirusmirus52downregulationofgab1regulatescellularproliferationanditalictoggleyesul138italicexpressionthroughmodulationofepidermalgrowthfactorreceptorsignalingpathways AT feliciadgoodrum humancytomegalovirusmirus52downregulationofgab1regulatescellularproliferationanditalictoggleyesul138italicexpressionthroughmodulationofepidermalgrowthfactorreceptorsignalingpathways AT jayanelson humancytomegalovirusmirus52downregulationofgab1regulatescellularproliferationanditalictoggleyesul138italicexpressionthroughmodulationofepidermalgrowthfactorreceptorsignalingpathways
_version_	1718427920502882304

Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and <italic toggle="yes">UL138</italic> Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways

Ejemplares similares