Tombusvirus-yeast interactions identify conserved cell-intrinsic viral restriction factors

Sasvari, Zsuzsanna; Gonzalez, Paulina Alatriste; Nagy, Peter D.

doi:10.3389/fpls.2014.00383

Cited by 25 publications

(18 citation statements)

References 114 publications

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“…In this yeast experimental system, cells are transformed to express the tombusviral p33 and p92 replication proteins, which function to replicate short tombusvirus replicons derived from viral defective interfering RNAs. Studies involving genome wide screens and yeast protoarrays revealed a subset of host factors associated with the viral replication machinery [32,33,34]. Homologues of many identified factors that have been identified in plants and investigations typically report parallel analysis of protein contributions to virus replication in yeast and in plants.…”

Section: Ubiquitin Proteasome System Supporting Virus Replication mentioning

confidence: 99%

Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum

Verchot

2016

Viruses

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The endoplasmic reticulum (ER) is central to plant virus replication, translation, maturation, and egress. Ubiquitin modification of ER associated cellular and viral proteins, alongside the actions of the 26S proteasome, are vital for the regulation of infection. Viruses can arrogate ER associated ubiquitination as well as cytosolic ubiquitin ligases with the purpose of directing the ubiquitin proteasome system (UPS) to new targets. Such targets include necessary modification of viral proteins which may stabilize certain complexes, or modification of Argonaute to suppress gene silencing. The UPS machinery also contributes to the regulation of effector triggered immunity pattern recognition receptor immunity. Combining the results of unrelated studies, many positive strand RNA plant viruses appear to interact with cytosolic Ub-ligases to provide novel avenues for controlling the deleterious consequences of disease. Viral interactions with the UPS serve to regulate virus infection in a manner that promotes replication and movement, but also modulates the levels of RNA accumulation to ensure successful biotrophic interactions. In other instances, the UPS plays a central role in cellular immunity. These opposing roles are made evident by contrasting studies where knockout mutations in the UPS can either hamper viruses or lead to more aggressive diseases. Understanding how viruses manipulate ER associated post-translational machineries to better manage virus–host interactions will provide new targets for crop improvement.

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Section: Ubiquitin Proteasome System Supporting Virus Replication mentioning

confidence: 99%

Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum

Verchot

2016

Viruses

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“…However, some cellular factors could act as CIRFs restricting virus replication (22,83,84). Among the several CIRFs against tombusviruses, Rsp5p and the WW-domain proteins are strong inhibitors, which are present in both yeast and plant cells (64,65).…”

Section: Rsp5p and Ww-domain Proteins Act As Cirfs Against Tombusvirumentioning

confidence: 99%

“…In addition to the WW-domain-containing host factors, other cellular factors with CIRF functions might also be involved in regulation of TBSV replication (22). To further test the possible regulatory functions of recruited cellular proteins, we chose two additional cellular CIRF factors that inhibit TBSV replication.…”

Section: Inhibition Of the Rna-binding And Protein-interaction Functimentioning

confidence: 99%

“…In addition to the subverted cellular proteins helping viral replication as susceptibility factors, many host proteins have been identified, which act as cell-intrinsic restriction factors (CIRFs) (11)(12)(13)(14)(15)(18)(19)(20)(21)(22). These factors might be components of the innate immune responses and used by the host for antiviral defense (23-26) or utilized by viruses as regulatory factors to keep the replication process under control (27).…”

Section: Importancementioning

confidence: 99%

“…The cellular ESCRT proteins, reticulons, and amphiphysins could be involved in membrane deformation occurring during VRC assembly (4,16,17). Altogether, it seems that the VRC assembly is a rather complex process driven by many factors; thus, it is likely regulated by viral and host factors for optimal replication in infected cells.In addition to the subverted cellular proteins helping viral replication as susceptibility factors, many host proteins have been identified, which act as cell-intrinsic restriction factors (CIRFs) (11)(12)(13)(14)(15)(18)(19)(20)(21)(22). These factors might be components of the innate immune responses and used by the host for antiviral defense (23-26) or utilized by viruses as regulatory factors to keep the replication process under control (27).…”

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

Barajas

Kovalev

Qin

et al. 2015

J Virol

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Replication of (؉)RNA viruses depends on several co-opted host proteins but is also under the control of cell-intrinsic restriction factors (CIRFs). By using tombusviruses, small model viruses of plants, we dissect the mechanism of inhibition of viral replication by cellular WW-domain-containing proteins, which act as CIRFs. By using fusion proteins between the WW domain and the p33 replication protein, we show that the WW domain inhibits the ability of p33 to bind to the viral RNA and to other p33 and p92 replication proteins leading to inhibition of viral replication in yeast and in a cell extract. Overexpression of WWdomain protein in yeast also leads to reduction of several co-opted host factors in the viral replicase complex (VRC). These host proteins, such as eEF1A, Cdc34 E2 ubiquitin-conjugating enzyme, and ESCRT proteins (Bro1p and Vps4p), are known to be involved in VRC assembly. Simultaneous coexpression of proviral cellular factors with WW-domain protein partly neutralizes the inhibitory effect of the WW-domain protein. We propose that cellular WW-domain proteins act as CIRFs and also as regulators of tombusvirus replication by inhibiting the assembly of new membrane-bound VRCs at the late stage of infection. We suggest that tombusviruses could sense the status of the infected cells via the availability of cellular susceptibility factors versus WWdomain proteins for binding to p33 replication protein that ultimately controls the formation of new VRCs. This regulatory mechanism might explain how tombusviruses could adjust the efficiency of RNA replication to the limiting resources of the host cells during infections. IMPORTANCEReplication of positive-stranded RNA viruses, which are major pathogens of plants, animals, and humans, is inhibited by several cell-intrinsic restriction factors (CIRFs) in infected cells. We define here the inhibitory roles of the cellular Rsp5 ubiquitin ligase and its WW domain in plant-infecting tombusvirus replication in yeast cells and in vitro using purified components. The WW domain of Rsp5 binds to the viral RNA-binding sites of p33 and p92 replication proteins and blocks the ability of these viral proteins to use the viral RNA for replication. The WW domain also interferes with the interaction (oligomerization) of p33 and p92 that is needed for the assembly of the viral replicase. Moreover, WW domain also inhibits the subversion of several cellular proteins into the viral replicase, which otherwise play proviral roles in replication. Altogether, Rsp5 is a CIRF against a tombusvirus, and it possibly has a regulatory function during viral replication in infected cells. P lus-stranded (ϩ)RNA viruses, which are widespread and emerging pathogens, replicate in the cytosol of infected cells by assembling membrane-bound viral replicase complexes (VRCs). The VRCs consist of the viral RNA and viral proteins, as well as co-opted host-coded proteins (1-8). Rapid progress has recently been made in understanding the functions of the viral replication proteins, including the v...

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Exploration of Plant Virus Replication Inside a Surrogate Host, Saccharomyces cerevisiae, Elucidates Complex and Conserved Mechanisms

Sasvari

Nagy

2016

Current Research Topics in Plant Virology

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Tombusvirus-yeast interactions identify conserved cell-intrinsic viral restriction factors

Cited by 25 publications

References 114 publications

Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum

Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum

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

Exploration of Plant Virus Replication Inside a Surrogate Host, Saccharomyces cerevisiae, Elucidates Complex and Conserved Mechanisms

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