Cyclophilin A Binds to the Viral RNA and Replication Proteins, Resulting in Inhibition of Tombusviral Replicase Assembly

Kovalev, Nikolay; Nagy, Peter D.

doi:10.1128/jvi.02101-13

Cited by 35 publications

(29 citation statements)

References 75 publications

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“…The published data support the model that binding of CypA and the plant orthologs to these viral components blocks the functions of the viral replication proteins in viral (+)RNA recruitment and VRC assembly (Figure 4) (Kovalev and Nagy, 2013). …”

Section: Characterization Of Antiviral Functions Of the Identified Cesupporting

confidence: 78%

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

2014

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To combat viral infections, plants possess innate and adaptive immune pathways, such as RNA silencing, R gene and recessive gene-mediated resistance mechanisms. However, it is likely that additional cell-intrinsic restriction factors (CIRF) are also involved in limiting plant virus replication. This review discusses novel CIRFs with antiviral functions, many of them RNA-binding proteins or affecting the RNA binding activities of viral replication proteins. The CIRFs against tombusviruses have been identified in yeast (Saccharomyces cerevisiae), which is developed as an advanced model organism. Grouping of the identified CIRFs based on their known cellular functions and subcellular localization in yeast reveals that TBSV replication is limited by a wide variety of host gene functions. Yeast proteins with the highest connectivity in the network map include the well-characterized Xrn1p 5′–3′ exoribonuclease, Act1p actin protein and Cse4p centromere protein. The protein network map also reveals an important interplay between the pro-viral Hsp70 cellular chaperone and the antiviral co-chaperones, and possibly key roles for the ribosomal or ribosome-associated factors. We discuss the antiviral functions of selected CIRFs, such as the RNA binding nucleolin, ribonucleases, WW-domain proteins, single- and multi-domain cyclophilins, TPR-domain co-chaperones and cellular ion pumps. These restriction factors frequently target the RNA-binding region in the viral replication proteins, thus interfering with the recruitment of the viral RNA for replication and the assembly of the membrane-bound viral replicase. Although many of the characterized CIRFs act directly against TBSV, we propose that the TPR-domain co-chaperones function as “guardians” of the cellular Hsp70 chaperone system, which is subverted efficiently by TBSV for viral replicase assembly in the absence of the TPR-domain co-chaperones.

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Section: Characterization Of Antiviral Functions Of the Identified Cesupporting

confidence: 78%

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

2014

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“…Members of the PPIase protein family (e.g., cyclophilins, FKBPs, and parvulins) are enzymes found in both eukaryotes and prokaryotes, participate in cell signaling, gene transcription and assist folding and localization of proteins, respectively (Hanes, 2015). More recently, Cyps were shown to facilitate dissociation of the human Papillomavirus Type 16 L1 and L2 capsid proteins from L2/DNA complexes following virus entry (Bienkowska-Haba et al, 2012), while CypA was shown to bind Tomato bushy stunt tombusvirus and inhibit tombusvirus replicase assembly (Kovalev and Nagy, 2013). Furthermore, Zhou et al (2016) showed that Cyp genes contribute to the development and virulence of Beauveria bassiana , an entomopathogenic fungus.…”

Section: Introductionmentioning

confidence: 99%

Implication of the Whitefly Bemisia tabaci Cyclophilin B Protein in the Transmission of Tomato yellow leaf curl virus

Kanakala

Ghanim

2016

Front. Plant Sci.

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Tomato yellow leaf curl virus (TYLCV) is a single-stranded (ssDNA) begomoviruses that causes severe damage to tomato and several other crops worldwide. TYLCV is exclusively transmitted by the sweetpotato whitefly, Bemisia tabaci in a persistent circulative and propagative manner. Previous studies have shown that the transmission, retention, and circulation of TYLCV in its vector involves interaction with insect and endosymbiont proteins, which aid in the transmission of the virus, or have a protective role in response to the presence of the virus in the insect body. However, only a low number of such proteins have been identified. Here, the role of B. tabaci Cyclophilin B (CypB) in the transmission of TYLCV protein was investigated. Cyclophilins are a large family of cellular prolyl isomerases that have many molecular roles including facilitating protein-protein interactions in the cell. One cyclophilin protein has been implicated in aphid-luteovirus interactions. We demonstrate that the expression of CypB from B. tabaci is altered upon TYLCV acquisition and retention. Further experiments used immunocapture-PCR and co-immunolocalization and demonstrated a specific interaction and colocalization between CypB and TYLCV in the the midgut, eggs, and salivary glands. Membrane feeding of anti-CypB antibodies and TYLCV-infected plants showed a decrease in TYLCV transmission, suggesting a critical role that CypB plays in TYLCV transmission. Further experiments, which used membrane feeding with the CypB inhibitor Cyclosporin A showed decrease in CypB-TYLCV colocalization in the midgut and virus transmission. Altogether, our results indicate that CypB plays an important role in TYLCV transmission by B. tabaci.

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“…7), we suggest that the CypA and TPR-domain proteins and the WWdomain proteins have different regulatory roles during TBSV replication in yeast. This is surprising because, similar to the WW domain, the TPR domain of Cpr7p and CypA also bind to the RPR region in p33 responsible for viral RNA binding (77,78).…”

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

confidence: 92%

“…These were the TPR-domain-containing cellular proteins (77) and cyclophilins (45). The TPR domain from Cyp40-like Cpr7p chaperone and the CypA (homolog of the yeast Cpr1p) cyclophilin have been shown to bind to the tombusvirus replication proteins (45,65,78). Similar to the strategy described above with the WW-domain protein (Fig.…”

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

confidence: 94%

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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Cyclophilin A Binds to the Viral RNA and Replication Proteins, Resulting in Inhibition of Tombusviral Replicase Assembly

Cited by 35 publications

References 75 publications

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

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

Implication of the Whitefly Bemisia tabaci Cyclophilin B Protein in the Transmission of Tomato yellow leaf curl virus

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

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