Human Cytomegalovirus Genomes Survive Mitosis via the IE19 Chromatin-Tethering Domain

Lyon, Shelby M.; Yetming, Kristen; Paulus, Christina; Nevels, Michael; Kalejta, Robert F.

doi:10.1128/mbio.02410-20

Cited by 10 publications

(25 citation statements)

References 75 publications

(102 reference statements)

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“…Their data also suggest that viral major immediate-early (IE) proteins of the IE1 family contribute to HCMV episome tethering. These findings are consistent with two other recent reports implicating IE1 family proteins in viral genome maintenance ( Tarrant-Elorza et al., 2014 ; Lyon et al., 2020 ). A role for IE1 in maintaining HCMV latency may come as a surprise, since the major IE promoter-enhancer (MIEP) appears to be highly repressed during latency in myeloid cells including monocytes ( Elder and Sinclair, 2019 ; Dooley and O’Connor, 2020 ).…”

Section: Host Interactions During CMV Latency and Reactivationsupporting

confidence: 93%

Editorial: Cytomegalovirus Pathogenesis and Host Interactions

Poole

Nevels

2021

Front. Cell. Infect. Microbiol.

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Editorial on the Research Topic Cytomegalovirus Pathogenesis and Host Interactions SCOPE OF THE RESEARCH TOPICHuman cytomegalovirus (HCMV) is a very widespread and highly prevalent b-herpesvirus, which sometimes causes mononucleosis following primary infection but is rarely associated with severe disease in immunocompetent individuals (Boeckh and Geballe, 2011;Griffiths et al., 2015). However, like all herpesviruses, HCMV establishes infections that last for the life of the host in part by residing in a dormant state referred to as 'latency ' (Sinclair and Poole, 2014;Dupont and Reeves, 2016). Reactivation from latency or primary infection can cause debilitating damage in unborn children or life-threatening disease in immunosuppressed patients including recipients of solid organ or hematopoietic cell transplants (Collins-McMillen et al., 2018;Heald-Sargent et al., 2020). Besides human cell culture systems of HCMV productive and latent infection (Peppenelli et al., 2021;Poole et al., 2021), mice infected with murine cytomegalovirus (MCMV) have served as invaluable models to understand host immune responses, viral immune evasion strategies and the mechanisms of pathogenesis (Brizic et al., 2018;Reddehase and Lemmermann, 2018). HCMV replicates productively in a wide variety of terminally differentiated cell types ('lytic' infection) while targeting select undifferentiated cells, including myeloid progenitors and monocytes, for latent infection (Sinclair and Poole, 2014;Goodrum, 2016). CMVs are highly sophisticated pathogens encoding hundreds of proteins and non-coding RNAs that engage in a myriad of host interactions (Stern-Ginossar et al., 2012;Weekes et al., 2014). The study of these interactions is constantly revealing new and surprising insights into both the replication and persistence strategies of the virus as well as the biology of the host cell and organism.The recently published Research Topic 'Cytomegalovirus Pathogenesis and Host Interactions' combines 28 articles (8 Original Research Articles, 10 Brief Research Reports, 8 Reviews, 1 Mini Review and this Editorial), involving 138 authors, 45 reviewers and 5 editors working in the field. Below, we are providing an overview of the articles published in this Research Topic, dividing them into the four sections 'innate and adaptive immune control of CMV pathogenesis' (11 articles), 'host interactions during CMV latency and reactivation' (6 articles), 'host interactions during productive CMV infection' (6 articles) and 'targeting CMV pathogenesis by anti-viral therapy' (4 articles).

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Section: Host Interactions During CMV Latency and Reactivationsupporting

confidence: 93%

Editorial: Cytomegalovirus Pathogenesis and Host Interactions

Poole

Nevels

2021

Front. Cell. Infect. Microbiol.

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“…Furthermore, hIE1 has been shown to contain a C-terminal chromatin tethering domain (CTD) that plays a role in association with mitotic chromosomes [ 25 , 26 , 39 ]. Immunofluorescence analyses revealed that rIE1 could neither bind to rats nor human mitotic chromatin ( Figure 8 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrated that the CTD is dispensable for productive replication in asynchronous fibroblast cells [ 8 , 25 ]. However, as suggested by a recent publication using a CTD-deficient recombinant in the Towne strain of HCMV, this domain may be important for maintaining the viral genome during mitosis [ 39 ]. If the CTD of hIE1 indeed acts as a genome maintenance factor, one may speculate that either RCMV lacks this function or encodes a different protein that serves to maintain viral genomes during mitosis.…”

Section: Discussionmentioning

confidence: 99%

Cross-Species Analysis of Innate Immune Antagonism by Cytomegalovirus IE1 Protein

Rothemund¹,

Scherer²,

Schilling³

et al. 2022

Viruses

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The human cytomegalovirus (CMV) immediate early 1 (IE1) protein has evolved as a multifunctional antagonist of intrinsic and innate immune mechanisms. In addition, this protein serves as a transactivator and potential genome maintenance protein. Recently, the crystal structures of the human and rat CMV IE1 (hIE1, rIE1) core domain were solved. Despite low sequence identity, the respective structures display a highly similar, all alpha-helical fold with distinct variations. To elucidate which activities of IE1 are either species-specific or conserved, this study aimed at a comparative analysis of hIE1 and rIE1 functions. To facilitate the quantitative evaluation of interactions between IE1 and cellular proteins, a sensitive NanoBRET assay was established. This confirmed the species-specific interaction of IE1 with the cellular restriction factor promyelocytic leukemia protein (PML) and with the DNA replication factor flap endonuclease 1 (FEN1). To characterize the respective binding surfaces, helix exchange mutants were generated by swapping hIE1 helices with the corresponding rIE1 helices. Interestingly, while all mutants were defective for PML binding, loss of FEN1 interaction was confined to the exchange of helices 1 and 2, suggesting that FEN1 binds to the stalk region of IE1. Furthermore, our data reveal that both hIE1 and rIE1 antagonize human STAT2; however, distinct regions of the respective viral proteins mediated the interaction. Finally, while PML, FEN1, and STAT2 binding were conserved between primate and rodent proteins, we detected that rIE1 lacks a chromatin tethering function suggesting that this activity is dispensable for rat CMV. In conclusion, our study revealed conserved and distinct functions of primate and rodent IE1 proteins, further supporting the concept that IE1 proteins underwent a narrow co-evolution with their respective hosts to maximize their efficacy in antagonizing innate immune mechanisms and supporting viral replication.

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“…Additionally, the IE protein facilitates the correct nuclear localization of the CMV genome during mitosis through the chromatin-tethering domain. The IE protein can also maintain the mitotic cell cycle of the host cells and induce cell proliferation [ 41 ]. In addition, CMV expresses the US28 protein, which induces IL-6 expression and STAT3 phosphorylation, both promoting paracrine signaling in oncogenesis [ 42 ].…”

Section: Mechanisms Of Cmv-related Glioma Tumorigenesismentioning

confidence: 99%

Cytomegalovirus and Glioblastoma: A Review of the Biological Associations and Therapeutic Strategies

Yang

Liu

Fang

et al. 2022

JCM

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Glioblastoma is the most common and aggressive malignancy in the adult central nervous system. Cytomegalovirus (CMV) plays a crucial role in the pathogenesis and treatment of glioblastoma. We reviewed the epidemiology of CMV in gliomas, the mechanism of CMV-related carcinogenesis, and its therapeutic strategies, offering further clinical practice insights. To date, the CMV infection rate in glioblastoma is controversial, while mounting studies have suggested a high infection rate. The carcinogenesis mechanism of CMV has been investigated in relation to various aspects, including oncomodulation, oncogenic features, tumor microenvironment regulation, epithelial–mesenchymal transition, and overall immune system regulation. In clinical practice, the incidence of CMV-associated encephalopathy is high, and CMV-targeting treatment bears both anti-CMV and anti-tumor effects. As the major anti-CMV treatment, valganciclovir has demonstrated a promising survival benefit in both newly diagnosed and recurrent glioblastoma as an adjuvant therapy, regardless of surgery and the MGMT promoter methylation state. Immunotherapy, including DC vaccines and adoptive CMV-specific T cells, is also under investigation, and preliminary results have been promising. There are still questions regarding the significance of CMV infection and the carcinogenic mechanism of CMV. Meanwhile, studies have demonstrated the clinical benefits of anti-CMV therapy in glioblastoma. Therefore, anti-CMV therapies are worthy of further recognition and investigation.

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Human Cytomegalovirus Genomes Survive Mitosis via the IE19 Chromatin-Tethering Domain

Cited by 10 publications

References 75 publications

Editorial: Cytomegalovirus Pathogenesis and Host Interactions

Editorial: Cytomegalovirus Pathogenesis and Host Interactions

Cross-Species Analysis of Innate Immune Antagonism by Cytomegalovirus IE1 Protein

Cytomegalovirus and Glioblastoma: A Review of the Biological Associations and Therapeutic Strategies

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