Dupont, L;
Du, L;
Poulter, M;
Choi, S;
McIntosh, M;
Reeves, MB;
(2019)
Src family kinase activity drives cytomegalovirus reactivation by recruiting MOZ histone acetyltransferase activity to the viral promoter.
Journal of Biological Chemistry
, 294
(35)
pp. 12901-12910.
10.1074/jbc.RA119.009667.
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Src family kinase activity drives cytomegalovirus reactivation by recruiting MOZ histone acetyltransferase activity to the v.pdf - Published Version Download (1MB) | Preview |
Abstract
Human cytomegalovirus (HCMV) latency and reactivation relies on a complex interplay between cellular differentiation, cell signaling pathways, and viral gene functions. HCMV reactivation in dendritic cells (DCs) is triggered by interleukin-6 (IL-6) and extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) signaling. However, activation of the same pathway fails to reactivate HCMV in other myeloid cell types, despite this signaling axis being active in those cells. We hypothesized that IL-6-induced ERK activation initiates the changes in chromatin structure required for viral reactivation, but that a concomitant signal is necessary to complete the changes in chromatin structure required for gene expression to occur. Using a differential phosphoproteomic approach in cells that do or do not support IL-6-induced viral reactivation, we identified the concomitant activation of a Src family kinase (SFK), hematopoietic cell kinase (HCK), specifically in DCs in response to IL-6. Pharmacological and genetic inhibition of HCK activity indicated that HCK is required for HCMV reactivation. Furthermore, the HCK/SFK activity was linked to the recruitment of the monocytic leukemia zinc finger protein (MOZ) histone acetyltransferase to the viral promoter, which promoted histone acetylation after ERK-mediated histone phosphorylation. Importantly, pharmacological and genetic inhibition of MOZ activity prevented reactivation. These results provide an explanation for the selective activation of viral gene expression in DCs by IL-6, dependent on concomitant SFK and ERK signaling. They also reveal a previously unreported role for SFK activity in the regulation of chromatin structure at promoters in eukaryotic cells via MOZ histone acetyltransferase activity.
| Type: | Article |
|---|---|
| Title: | Src family kinase activity drives cytomegalovirus reactivation by recruiting MOZ histone acetyltransferase activity to the viral promoter |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.RA119.009667 |
| Publisher version: | https://doi.org/10.1074/jbc.RA119.009667 |
| Language: | English |
| Additional information: | Copyright © 2019 Dupont et al. Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0). |
| Keywords: | cell signaling, chromatin modification, cytomegalovirus reactivation, epigenetic regulation, gene expression, haematopoietic cell kinase, herpesvirus, histone acetylation, lysine acetyltransferase 6A (KAT6A), phosphproteomics |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10077491 |
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