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

ABSTRACT: 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.

SUBMITTER: Sasvari Z

PROVIDER: S-EPMC4127529 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Sasvari Zsuzsanna Z Alatriste Gonzalez Paulina P Nagy Peter D PD

Frontiers in plant science 20140811

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 be ...[more]

PMID: 25157258

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Project description:Recent genome-wide screens reveal that the host cells express an arsenal of proteins that inhibit replication of plus-stranded RNA viruses by functioning as cell-intrinsic restriction factors of viral infections. One group of cell-intrinsic restriction factors against tombusviruses contains tetratricopeptide repeat (TPR) domains that directly interact with the viral replication proteins. In this paper, we find that the TPR domain-containing Hop-like stress-inducible protein 1 (Sti1p) cochaperone selectively inhibits the mitochondrial membrane-based replication of Carnation Italian ringspot tombusvirus (CIRV). In contrast, Sti1/Hop does not inhibit the peroxisome membrane-based replication of the closely related Tomato bushy stunt virus (TBSV) or Cucumber necrosis virus (CNV) in a yeast model or in plants. Deletion of STI1 in yeast leads to up to a 4-fold increase in CIRV replication, and knockdown of the orthologous Hop cochaperone in plants results in a 3-fold increase in CIRV accumulation. Overexpression of Sti1p derivatives in yeast reveals that the inhibitory function depends on the TPR1 domain known to interact with heat shock protein 70 (Hsp70), but not on the TPR2 domain interacting with Hsp90. In vitro CIRV replication studies based on isolated mitochondrial preparations and purified recombinant proteins has confirmed that Sti1p, similar to the TPR-containing Cyp40-like Cpr7p cyclophilin and the Ttc4 oncogene-like Cns1 cochaperone, is a strong inhibitor of CIRV replication. Sti1p interacts and colocalizes with the CIRV replication proteins in yeast. Our findings indicate that the TPR-containing Hop/Sti1 cochaperone could act as a cell-intrinsic virus restriction factor of the mitochondrial CIRV, but not against the peroxisomal tombusviruses in yeast and plants.The host cells express various cell-intrinsic restriction factors that inhibit the replication of plus-stranded RNA viruses. In this paper, the authors find that the Hop-like stress-inducible protein 1 (Sti1p) cochaperone selectively inhibits the mitochondrial membrane-based replication of Carnation Italian ringspot tombusvirus (CIRV) in yeast. Deletion of STI1 in yeast or knockdown of the orthologous Hop cochaperone in plants leads to increased CIRV replication. In addition, overexpression of Sti1p derivatives in yeast reveals that the inhibitory function depends on the TPR1 domain known to interact with heat shock protein 70 (Hsp70), but not on the TPR2 domain interacting with Hsp90. In vitro CIRV replication studies based on isolated mitochondrial preparations and purified recombinant proteins have confirmed that Sti1p is a strong inhibitor of CIRV replication. The authors' findings reveal that the Hop/Sti1 cochaperone could act as a cell-intrinsic restriction factor against the mitochondrial CIRV, but not against the related peroxisomal tombusviruses.

Project description:The killer phenomenon in yeast (Saccharomyces cerevisiae) not only provides the opportunity to study host-virus interactions in a eukaryotic model but also represents a powerful tool to analyze potential coadaptional events and the role of killer yeast in biological diversity. Although undoubtedly having a crucial impact on the abundance and expression of the killer phenotype in killer-yeast harboring communities, the influence of a particular toxin on its producing host cell has not been addressed sufficiently. In this study, we describe a model system of two K1 killer yeast strains with distinct phenotypical differences pointing to substantial selection pressure in response to the toxin secretion level. Transcriptome and lipidome analyses revealed specific and intrinsic host cell adaptions dependent on the amount of K1 toxin produced. High basal expression of genes coding for osmoprotectants and stress-responsive proteins in a killer yeast strain secreting larger amounts of active K1 toxin implies a generally increased stress tolerance. Moreover, the data suggest that immunity of the host cell against its own toxin is essential for the balanced virus-host interplay providing valuable hints to elucidate the molecular mechanisms underlying K1 immunity and implicating an evolutionarily conserved role for toxin immunity in natural yeast populations.IMPORTANCE The killer phenotype in Saccharomyces cerevisiae relies on the cytoplasmic persistence of two RNA viruses. In contrast to bacterial toxin producers, killer yeasts necessitate a specific immunity mechanism against their own toxin because they bear the same receptor populations as sensitive cells. Although the killer phenomenon is highly abundant and has a crucial impact on the structure of yeast communities, the influence of a particular toxin on its host cell has been barely addressed. In our study, we used two derivatives secreting different amount of the killer toxin K1 to analyze potential coadaptional events in this particular host/virus system. Our data underline the dependency of the host cell's ability to cope with extracellular toxin molecules and intracellular K1 molecules provided by the virus. Therefore, this research significantly advances the current understanding of the evolutionarily conserved role of this molecular machinery as an intrinsic selection pressure in yeast populations.

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

Publications

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

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