Recent genome-wide screens with multiple viruses have identified several host proteins, which inhibit RNA virus accumulation and act as restriction factors against viruses. Unfortunately, the restriction functions of these host factors are not yet defined for important human viruses. Among the identified inhibitory host proteins are the family of WW-domain proteins, which are effective against several viruses. WW-domain proteins are abundant proteins participating in protein interactions and they are involved in several diseases, such as human cancers, inherited diseases and viral infections. Progress in our understanding of the mechanisms of host factors is slow due to functional redundancy or lack of knowledge about their functions. However, easily tractable virus - host systems, such as Tomato bushy stunt virus (TBSV) and yeast as a model host can contribute to our understanding of the functions of these host proteins. This project will likely advance our understanding of the role of host WW-domain proteins in virus-host interactions. This advance could immensely help other scientists working with less tractable, but devastating viral pathogens for which similar studies are currently not yet feasible. The following are the major strengths of the proposal: (i) Host restriction factors have clear negative impact on viruses. (ii) The restriction function of WW-domain proteins will be explored against tombusviruses and insect nodaviruses. (iii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iv) The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication, host-virus interactions and the viral pathogenesis.
Viruses, which are important and emerging human, animal and plant pathogens, are greatly affected by host restriction factors. We find in high throughput screens that inactivation of selected host WW-domain proteins facilitated robust RNA virus replication. The proposed work will explore the inhibitory roles of host WW-domain proteins in virus infection that could facilitate the development of novel antiviral approaches.
|Xu, Kai; Nagy, Peter D (2017) Sterol Binding by the Tombusviral Replication Proteins Is Essential for Replication in Yeast and Plants. J Virol 91:|
|Barajas, Daniel; Kovalev, Nikolay; Qin, Jun et al. (2015) Novel mechanism of regulation of tomato bushy stunt virus replication by cellular WW-domain proteins. J Virol 89:2064-79|
|Pogany, Judit; Nagy, Peter D (2015) Activation of Tomato Bushy Stunt Virus RNA-Dependent RNA Polymerase by Cellular Heat Shock Protein 70 Is Enhanced by Phospholipids In Vitro. J Virol 89:5714-23|
|Nagy, Peter D (2015) Viral sensing of the subcellular environment regulates the assembly of new viral replicase complexes during the course of infection. J Virol 89:5196-9|
|Lin, Jing-Yi; Nagy, Peter D (2013) Identification of novel host factors via conserved domain search: Cns1 cochaperone is a novel restriction factor of tombusvirus replication in yeast. J Virol 87:12600-10|