Abstract
RNA viruses exploit host cells by co-opting host factors and lipids and escaping host antiviral responses. Previous genome-wide screens with Tomato bushy stunt virus (TBSV) in the model host yeast have identified 18 cellular genes that are part of the actin network. In this paper, we show that the p33 viral replication factor interacts with the cellular cofilin (Cof1p), which is an actin depolymerization factor. Using temperature-sensitive (ts) Cof1p or actin (Act1p) mutants at a semi-permissive temperature, we find an increased level of TBSV RNA accumulation in yeast cells and elevated in vitro activity of the tombusvirus replicase. We show that the large p33 containing replication organelle-like structures are located in the close vicinity of actin patches in yeast cells or around actin cable hubs in infected plant cells. Therefore, the actin filaments could be involved in VRC assembly and the formation of large viral replication compartments containing many individual VRCs. Moreover, we show that the actin network affects the recruitment of viral and cellular components, including oxysterol binding proteins and VAP proteins to form membrane contact sites for efficient transfer of sterols to the sites of replication. Altogether, the emerging picture is that TBSV, via direct interaction between the p33 replication protein and Cof1p, controls cofilin activities to obstruct the dynamic actin network that leads to efficient subversion of cellular factors for pro-viral functions. In summary, the discovery that TBSV interacts with cellular cofilin and blocks the severing of existing filaments and the formation of new actin filaments in infected cells opens a new window to unravel the way by which viruses could subvert/co-opt cellular proteins and lipids. By regulating the functions of cofilin and the actin network, which are central nodes in cellular pathways, viruses could gain supremacy in subversion of cellular factors for pro-viral functions.
Highlights
Plus-stranded (+)RNA viruses, which are important pathogens of plants, animals and humans, co-opt a number of host-coded proteins and lipids to facilitate the replication process [1,2,3,4,5,6]
The authors show that Tomato bushy stunt virus (TBSV) interacts with cofilin actin depolymerization factor leading to inhibition of the dynamic function of the actin network in infected cells
Subversion of the actin network by TBSV is a key step for the virus to gain access to cellular resources required for virus replication
Summary
Plus-stranded (+)RNA viruses, which are important pathogens of plants, animals and humans, co-opt a number of host-coded proteins and lipids to facilitate the replication process [1,2,3,4,5,6]. These viruses remodel host membranes and alter host cellular pathways to take advantage of host resources and to avoid recognition by host antiviral defenses. The p92pol has RNA-dependent RNA polymerase (RdRp) activity and binds to p33 to assemble the membrane-bound functional viral replicase complex (VRC) [14,19,21,22,23,24]
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