Adriana Svrlanska

Suche


B3 Interference of the viral effector proteins pp71 and IE1 with ND10-mediated intrinsic immunity against human cytomegalovirus infections

Principal investigator
Thomas Stamminger

Mentor


Modulation of epigenetic regulatory processes through the IE2 protein of human cytomegalovirus

Human cytomegalovirus (HCMV), which is also known as human herpesvirus type 5 (HHV-5), is a member of the family of Herpesviridae. This family of enveloped DNA-viruses is characterized by its common virion morphology, a lytic replication and their ability to establish a life-long persistence in their hosts. Epigenetic control of human cytomegalovirus (HCMV) gene expression plays a key role in determining the outcome of infection. Thus, HCMV has to cope with, modulate or utilize the host cell’s chromatin machinery to promote efficient lytic replication or establish a latent state. Especially the major immediate-early enhancer-promoter (MIEP) is one of the main targets to chromatin-regulating proteins. The host cell repressor complex PRC2 (Polycomb repressive complex 2), consisting of the catalytic subunit EZH2 and the regulatory, non-catalytic subunits EED, Suz12 and RbAp46/48, has recently been shown to contribute to chromatin-based regulation of HCMV infection. Through its histone methyltransferase activity, EZH2 catalyzes trimethylation of histone 3 at lysine 27 which represents a hallmark of facultative heterochromatin. It was shown that PRC2 plays a key role during HCMV latency, during which viral transcription is silenced almost completely. PRC2 is recruited to the MIEP via the viral long non-coding RNA lncRNA4.9 where it is able to establish repressive chromatin, thereby suppressing lytic replication. Interestingly, PRC2 activity was also shown to be crucial for productive infection. In this case, it is responsible for the silencing of GFI1, a cellular repressor of HCMV MIEP. In former studies of our group, an interaction was discovered between EED, the regulatory subunit of PRC2, and the viral immediate early protein IE2. Since IE2 is an essential regulatory protein acting early during HCMV infection, we speculate that HCMV is able to regulate PRC2 function via this interaction. Therefore, the aim of this thesis is the characterization of the IE2-EED interaction and the elucidation of its function during lytic as well as latent HCMV infection.

.

Figure: Schematic overview of the functions of PRC2 during latent and lytic HCMV infection.
In the upper panel, the role of PRC2 during lyitic HCMV infection is depicted. As reported by Abraham and Kulesza (J. Virol., 2013) and Rossetto et al. (PLoS Pathog., 2014), PRC2 is actively recruited to viral genomes, where it contributes to the establishment of heterochromatin and the silencing of viral gene expression. As depicted in the lower panel, PCR2 also contributes to HCMV lytic infection by the downregulation of the cellular repressor GFI1 (Sourvinos et al., J. Virol., 2014).

 

 

Presentations

October 2015

2nd International SFB 796 Conference: Mechanisms of microbial host cell manipulation: From plants to humans, Erlangen, Germany
”Elucidating the role of Polycomb repressive complex 2 (PRC2) for the lytic replication of human cytomegalovirus”

Poster
     
July 2015

7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany
”Modulation of Polycomb repressive complex 2 activity by human Cytomegalovirus effector protein IE2”

Poster