| Abstract |
Human Cytomegalovirus (HCMV, HHV5) is a double stranded DNA beta-herpesvirus, which infects 50–90% of general population. HCMV infection has severe side-effects and correlated mortality in organ-transplant recipients, immunodeficient humans and newborns (congenital infection (cCMV)). Herein, it is investigated the epigenetic modulation of HCMV latency. The pioneer seeds of this project were the findings of a paper published by Sourvinos et al.,2014(226), indicated that immediate-early gene transcription and HCMV infection of human foreskin fibroblasts (HFFs) are dependent on histone H3K27 trimethylation, which is under the tight regulation of EZH2, JARID2, NDY1/KDM2B and JMJD3.
This project demonstrated for the very first time the interplay between Akt, EZH2 and GFI-1 in the context of HCMV infection. These scientific data represent that constitutively active Akt1 inhibits the infection of HCMV- infected HFFs, as opposed to active Akt3 which increases HCMV titer, favouring in this way the HCMV infection. Moreover, it is suggested the possible mechanism through which the constitutively active Akt1 blocks HCMV infection. This is owing to the inactivation of EZH2, via phosphorylation at Ser21 residue. It has already been indicated that Akt phosphorylates EZH2 at Ser21 and suppresses its methyltransferase activity by impeding EZH2 binding to histone H3, which results in a decrease of lysine 27 trimethylation and derepression of silenced genes.(225)
Moreover, Western Immunoblotting reveals that the mock cells own active Akt1 levels. In parallel, it is validated the phosphorylation of Akt3 in HCMV-infected HFFs expressing Akt3, Akt3 + myc EZH2 and Akt3 + myc EZH2 + shEZH2 3’UTR. Supporting the evidence of (226), we experimentally demonstrated that the mock cells possess elevated levels of the transcriptional repressor GFI-1. In contrast, GFI-1 is downregulated in HCMV-infected HFFs, irrespective of their EZH2 silencing status. Taken all the above into consideration, GFI-1 could be easily considered as a promising biomarker for HCMV infection. Targeting this molecule, especially upregulating GFI-1 expression might have therapeutic applications in HCMV infection in the forthcoming years.
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Constitutively active Akt1 interferes with HCMV infection by inactivating EZH2
