Global Genomics and Proteomics Approaches to Identify Host Factors as Targets to Induce Resistance Against Tomato Bushy Stunt Virus

Abstract

The success of RNA viruses as pathogens of plants, animals, and humans depends on their ability to reprogram the host cell metabolism to support the viral infection cycle and to suppress host defense mechanisms. Plus-strand (+)RNA viruses have limited coding potential necessitating that they co-opt an unknown number of host factors to facilitate their replication in host cells. Global genomics and proteomics approaches performed with Tomato bushy stunt virus (TBSV) and yeast (Saccharomyces cerevisiae) as a model host have led to the identification of 250 host factors affecting TBSV RNA replication and recombination or bound to the viral replicase, replication proteins, or the viral RNA. The roles of a dozen host factors involved in various steps of the replication process have been validated in yeast as well as a plant host. Altogether, the large number of host factors identified and the great variety of cellular functions performed by these factors indicate the existence of a truly complex interaction between TBSV and the host cell. This review summarizes the advantages of using a simple plant virus and yeast as a model host to advance our understanding of virus-host interactions at the molecular and cellular levels. The knowledge of host factors gained can potentially be used to inhibit virus replication via gene silencing, expression of dominant negative mutants, or design of specific chemical inhibitors leading to novel specific or broad-range resistance and antiviral tools against (+)RNA plant viruses.

Novel Mechanism of Regulation of Tomato Bushy Stunt Virus Replication by Cellular WW-Domain Proteins

“…The host proteins interacted with the viral replication proteins and viral RNA or affected TBSV replication and recombination when deleted/downregulated or overexpressed in host cells (11,13,(40)(41)(42)(43)(44)(45)(46)(47)(48). Cataloging of the host factors affecting TBSV replication is one of the most complete among pathogens at a single cell level, thus facilitating mechanistic studies.…”

The Hop-Like Stress-Induced Protein 1 Cochaperone Is a Novel Cell-Intrinsic Restriction Factor for Mitochondrial Tombusvirus Replication

“…We have performed several genome-wide screens of yeast genes by using different global proteomics approaches that have led to the identification of over 500 host genes/proteins putatively involved in TBSV replication or recombination (17,19,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). The abovementioned systematic screens have identified host stimulatory and restriction factors of TBSV replication.…”

The GEF1 Proton-Chloride Exchanger Affects Tombusvirus Replication via Regulation of Copper Metabolism in Yeast

“…ecent genome-wide screens have revealed that replication of RNA viruses inside the infected cells depends on hundreds of factors, most of which have not been characterized (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). In addition, RNA viruses extensively rewire the cells by changing metabolic, secretory, and trafficking pathways, reorganize host membranes, and alter quality control mechanisms (17,18).…”

“…Host factors affecting viral replication are intensively studied using Tomato bushy stunt tombusvirus (TBSV), which is among the most advanced model RNA viruses (10,18,40). The two replication proteins encoded by TBSV genes are the p33 replication cofactor, which is an RNA chaperone, and the p92 pol RNA-dependent RNA polymerase (RdRp) (41,42).…”