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Review
. 2020 Apr 29;48(2):667-675.
doi: 10.1042/BST20191110.

Cell signaling and cytomegalovirus reactivation: what do Src family kinases have to do with it?

Matthew B Reeves  1
Affiliations
Review

Cell signaling and cytomegalovirus reactivation: what do Src family kinases have to do with it?

Matthew B Reeves. Biochem Soc Trans. .

Abstract

Primary infection with human cytomegalovirus (HCMV) is usually asymptomatic and leads to the establishment of lifelong latent infection. A major site of latency are the CD34+ hematopoietic progenitor cells. Importantly, normal cellular differentiation of CD34+ cells to a macrophage or dendritic cell phenotype is concomitant with viral reactivation. Molecular studies of HCMV latency have shown that the latent viral genome is associated with histone proteins and that specific post-translational modifications of these histones correlates with the transcriptional activity of the genome arguing that expression of key viral genes that dictate latency and reactivation are subject to the rules of the histone code hypothesis postulated for the regulation of eukaryotic gene expression. Finally, many studies now point to a key role for multiple signaling pathways to provide the cue for HCMV reactivation. The challenge now is to understand the complex interplay between cell identity, transcriptional regulation and cell signaling that occurs to promote reactivation and, additionally, how HCMV may further manipulate these events to support reactivation. Understanding how HCMV utilizes these pathways to drive HCMV reactivation will provide new insight into the mechanisms that govern viral and host gene expression and, potentially, illuminate new, host-directed, therapeutic opportunities to support our attempts to control this important medical pathogen of immune-compromised individuals.

Keywords: Src family kinases; cell signaling; chromatin; cytomegalovirus; hematopoiesis; latency.

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Conflict of interest statement

The author declares that there are no competing interests associated with this manuscript.

Figures

Figure 1.
Figure 1.. Model for IL-6 induced reactivation in dendritic cells.
The MIEP of HCMV is associated with heterochromatin in latently infected CD34+ cells (A). Concomitant differentiation to a dendritic cell phenotype and activation of inflammatory IL-6 signaling initiates ERK–MAPK and SFK signaling. The activation of ERK promotes activation of mitogen and stress-activated kinases 1 and 2 (MSKs) which recognize the CREB transcription factor bound to the MIEP (B). Recruitment of MSK via CREB to the MIEP promotes dual phosphorylation of CREB and also histone H3 at serine 10 (C). Phosphorylation of serine 10 de-stabilizes the binding of HP-1 to methylated lysine 9 residues promoting its dissociation from the MIEP (D). This activation of SFK promotes the recruitment of MOZ histone acetyltransferase activity to the MIEP (D) which drives histone acetylation facilitating the robust induction of MIE gene expression (E) — the first event in full viral reactivation.
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