Studentship: Interaction between the neurovirulence protein from herpesvirus and the ER-resident TF:structural, biochemical and physiological insights
Lead Research Organisation:
The Pirbright Institute
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Marek's disease virus (MDV) is an oncogenic avian herpesvirus that induces malignant T-cell lymphomas and neurological disorders in its natural host, chicken. Although tropism for the central nervous systems is consistently associated with highly virulent MDV strains, the mechanism of MDV-mediated neuropathology is still poorly understood.
For the first time, phosphoprotein-14 (pp14), an immediate early protein from MDV1, has been identified as a neurovirulence factor. Furthermore, cAMP Response Element-Binding protein 3 (CREB3) has been identified as a cellular ligand for pp14 through which the viral protein may mediate the neurovirulence.
CREB3 is a membrane-bound transcription factor that has recently been shown to be activated in response to DNA and RNA viral infections. Although transcription factors of the CREB3 subfamily are understood to be activated through regulated intra-membrane proteolysis (RIP) the physiological stimuli for proteolytic activation of discrete transcription factors in the CREB3 subfamily and their physiological targets remain to be identified and characterised.
The aim of this project is to use a combination of biochemical, reverse genetic and structural approaches to derive new knowledge in pp14-CREB3-mediated neurovirulence.
For the first time, phosphoprotein-14 (pp14), an immediate early protein from MDV1, has been identified as a neurovirulence factor. Furthermore, cAMP Response Element-Binding protein 3 (CREB3) has been identified as a cellular ligand for pp14 through which the viral protein may mediate the neurovirulence.
CREB3 is a membrane-bound transcription factor that has recently been shown to be activated in response to DNA and RNA viral infections. Although transcription factors of the CREB3 subfamily are understood to be activated through regulated intra-membrane proteolysis (RIP) the physiological stimuli for proteolytic activation of discrete transcription factors in the CREB3 subfamily and their physiological targets remain to be identified and characterised.
The aim of this project is to use a combination of biochemical, reverse genetic and structural approaches to derive new knowledge in pp14-CREB3-mediated neurovirulence.
Planned Impact
unavailable
Publications
Sabaratnam K
(2019)
Insights from the crystal structure of the chicken CREB3 bZIP suggest that members of the CREB3 subfamily transcription factors may be activated in response to oxidative stress.
in Protein science : a publication of the Protein Society
| Description | cAMP response element binding Protein 3 (CREB3) is an endoplasmic reticulum (ER) membrane-bound transcription factor, which belongs to the basic leucine zipper (bZIP) superfamily of eukaryotic transcription factors. CREB3 plays a role in the ER-stress induced unfolded protein response (UPR) and is a multifunctional cellular factor implicated in a number of biological processes including cell proliferation and migration, tumor suppression, and immune-related gene expression. To gain structural insights into the transcription factor, we determined the crystal structure of the conserved bZIP domain of chicken CREB3 (chCREB3) to a resolution of 3.95 Å. The X-ray structure provides evidence that chCREB3 can form a stable homodimer. The chCREB3 bZIP has a structured, pre-formed DNA binding region, even in the absence of DNA, a feature that could potentially enhance both the DNA binding specificity and affinity of chCREB3. Significantly, the homodimeric bZIP possesses an intermolecular disulfide bond that connects equivalent cysteine residues of the parallel helices in the leucine zipper region. This disulfide bond in the hydrophobic core of the bZIP may increase the stability of the homodimer under oxidizing conditions. Moreover, sequence alignment of bZIP sequences from chicken, human, and mouse reveals that only members of the CREB3 subfamily contain this cysteine residue, indicating that it could act as a redox-sensor. |
| Exploitation Route | The finding that the activity of these transcription factors may be redox-regulated demonstrated that they may be activated in response to oxidative stress. These biochemical findings supported by structural data are valuable in regulating cell processes. |
| Sectors | Agriculture Food and Drink |
| Description | Presentation at the Microbiology Society meeting |
| Organisation | Microbiology Society |
| Country | United Kingdom |
| Sector | Learned Society |
| PI Contribution | PhD student presented her work at the meeting |
| Collaborator Contribution | The partners organised the meeting |
| Impact | Keshalini Sabaratnam presented the poster on 'The interaction between the MDV neurovirulence factor pp14 and the host transcription regulator, CREB3' at the Society's annual meeting |
| Start Year | 2016 |
| Description | AN INTERVIEW WITH PROFESSOR VENUGOPAL NAIR |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Professor Venugopal Nair is a Research Group Leader at The Pirbright Institute, a visiting Professor of Avian Virology at the Department of Zoology, and a Jenner Investigator at the Jenner Institute, University of Oxford. He is also a member of the Microbiology Society, and in this interview, he tells us more about his research into viral diseases of livestock. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://microbiologysociety.org/membership/meet-our-members/focus-area-viruses/an-interview-with-pro... |
| Description | Interaction between MDV neurovirulence factor pp14 and the host transcription regulator CREB3 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | The activity was at the Microbiology Society meeting |
| Year(s) Of Engagement Activity | 2016 |