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H2020Individual fellowship2017–2019

VGAP · The Viral Genome Associated Proteome

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2017-02-01 → 2019-07-30
EU contribution
€171,461
Participants
1
Scheme
MSCA-IF-EF-RI

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Results in brief

The Viral Genome Associated Proteome

Herpesviruses have evolved sophisticated ways to subvert the immune system during millions of years of coevolution with their respective hosts. The nine human members of the herpesvirus family include important human pathogens like Herpes-simplex viruses-1 and -2 (HSV-1 and HSV-2), Varicella-Zoster Virus (VZV), Human Cytomegalovirus (HCMV), Human Herpesviruses-6A, -6B and -7 and the tumor viruses Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV). A hallmark of herpesvirus infections is the establishment of lifelong latency, for example about 3.7 billion people alone are infected with HSV-1 worldwide, and even more by HHV-6, -7 and EBV. The goal of this project was the identification of novel restriction or host factors of herpesviruses that are involved or interfere with initiation of herpesviral gene expression and replication. Therefore a new method called HyCCAPP should be developed in order to discover new factors that associate with the viral genome upon nuclear entry. Although the initially proposed approach was not successful, we used alternative methods, namely CRISPRainbow- and EdC-labelling of viral genomes that allowed us to identify SMCHD1 as a novel restriction factor for herpesviruses that is associated with viral genomes. SMCHD1 is an important human protein, and mutations in SMCHD1 have been shown to be the cause of two genetic diseases, Facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphtalmia syndrome (BAMS). We characterized SMCHD1 in detail as antiviral protein and could even show viral antagonism of SMCHD1-mediated restriction by a protein of KSHV, further corroborating the importance of SMCHD1 in antiviral immunity. We hope that our discovery of a new antiviral restriction factor may help to understand the pathogenicity of herpesviral disease and contribute to the development of new anti-herpesviral drugs in the future.

Data: CORDIS, © European Union

Project objective

The aim of this study is to analyze the comprehensive proteome associated with viral DNA. This systems biology approach that will combine functional proteomics and genomics has the name Viral Genome Associated Proteome (VGAP). It is based on a modification and refinement of the Hybridization Capture of Chromatin Associated Proteins for Proteomics (HyCCAPP) technology. All proteins associated with viral DNA, initially using Herpes simplex virus for proof of concept, will be cross-linked by paraformaldehyde treatment, the viral DNA will be selectively precipitated, and all proteins associated with the viral genome will be analyzed by mass spectrometry. The results will reveal all cellular and viral proteins that physically interact with the viral genome at a certain time and that are involved among others in regulation of viral genome structure, viral gene expression, DNA repair and cellular intrinsic immunity. The development of VGAP, a new method for the specific analysis of the viral genome-associated proteome will provide a new tool for the research of DNA viruses. In theory VGAP should be applicable to all DNA viruses, and we think it will be possible to analyze proteins associated with the DNA of all DNA viruses, so the entire field of virology should profit from the establishment of viral HyCCAPP. DNA viruses include important human pathogens like herpesviruses, human papillomaviruses and adenoviruses. A plethora of novel viral DNA-protein interactions will be discovered that will spark new research projects and can serve as new targets for antiviral therapy and vaccination strategies. Although beyond the scope of this proposal, so far unknown cellular proteins that are needed for efficient viral replication can be used for screening of small molecule libraries and novel small molecule inhibitors identified for antiviral therapy.

Original text from CORDIS.

Participants

  • UNIVERSITATSKLINIKUM ERLANGEN · ErlangenCoordinatorGermany

Links

Data: CORDIS, © European Union