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

Xu, Kai; Lin, Jingyi; Nagy, Peter D.

doi:10.1128/jvi.00561-14

Cited by 24 publications

(28 citation statements)

References 131 publications

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“…benthamiana (Xu et al . ). Besides its role in these biotic stresses, the role of HOP during the plant response to ER stress or to any other abiotic stresses remains largely unknown.…”

Section: Introductionmentioning

confidence: 97%

“…In plants, HOP homologues have been described in different species as soybean (Zhang et al 2003), wheat (Fellerer et al 2011), rice (Nakashima et al 2008;Chen et al 2010), N. benthamiana (Xu et al 2014) and by in silico searches in Arabidopsis (Prasad et al 2010). In some of these organisms, HOP interaction with cytosolic HSP90 has been reported (Zhang et al 2003;Chen et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…However, in vivo complexes with HSP70 have not been described so far in plants, although HOP was detected associated to HSP70 and HSP90 in wheat germ lysate . Additionally, HOP has been recently involved in rice blast resistance (Chen et al 2010) and as a cell-intrinsic virus restriction factor of the mitochondrial Carnation Italian Ringspot Tombusvirus (CIRV) in N. benthamiana (Xu et al 2014). Besides its role in these biotic stresses, the role of HOP during the plant response to ER stress or to any other abiotic stresses remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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HOP3, a member of the HOP family in Arabidopsis, interacts with BiP and plays a major role in the ER stress response

Fernández-Bautista

Fernández‐Calvino

Muñoz

et al. 2017

Plant Cell & Environment

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HSP70-HSP90 organizing protein (HOP) is a well-studied family of cytosolic cochaperones. However, the possible role of HOP during the endoplasmic reticulum (ER) stress response and the identity of its interactors within the ER were not previously addressed in any eukaryote. We have demonstrated that Arabidopsis HOP3, whose function was not studied before, interacts in vivo with cytosolic HSP90 and HSP70, and, unexpectedly, with binding immunoglobulin protein (BiP), a HSP70 ER-resident protein. Although BiP lacks the domain described in other eukaryotes for HOP-HSP70 binding, it interacts with HOP3 through a non-canonical association to its nucleotide binding domain. Consistent with this interaction with BiP, HOP3 is partially localized at the ER. Moreover, HOP3 is induced both at transcript and protein levels by unfolded protein response (UPR) inducer agents by a mechanism dependent on inositol-requiring enzyme 1 (IRE1). Importantly, hop3 loss-of-function mutants show a reduction in pollen germination and a hypersensitive phenotype in the presence of ER stress inducer agents, a phenotype that is reverted by the addition of the chemical chaperone tauroursodeoxycholic acid (TUDCA). All these data demonstrate, for the first time in any eukaryote, a main role of HOP as an important regulator of the ER stress response, a process intimately linked in plants to important specific developmental programs and to environmental stress sensing and response.

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“…benthamiana (Xu et al . ). Besides its role in these biotic stresses, the role of HOP during the plant response to ER stress or to any other abiotic stresses remains largely unknown.…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HOP3, a member of the HOP family in Arabidopsis, interacts with BiP and plays a major role in the ER stress response

Fernández-Bautista

Fernández‐Calvino

Muñoz

et al. 2017

Plant Cell & Environment

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“…For measuring the effects of TBSV p33 single amino acid mutations on TBSV replicon RNA (repRNA) replication in yeast, yeast strain BY4741 was transformed with pYES-T92 (40) together with pESC-T33/DI72, pESC-T33-Y42P/DI72, pESC-T33-Y83P/DI72, pESC-T100P-Y42P/DI72, or pESC-T33-Y151P/ DI72. Induction of TBSV repRNA replication, total RNA extraction, and RNA analysis by Northern blotting were described previously (44).…”

Section: Methodsmentioning

confidence: 99%

Sterol Binding by the Tombusviral Replication Proteins Is Essential for Replication in Yeast and Plants

Nagy

2017

J Virol

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Membranous structures derived from various organelles are important for replication of plus-stranded RNA viruses. Although the important roles of co-opted host proteins in RNA virus replication have been appreciated for a decade, the equally important functions of cellular lipids in virus replication have been gaining full attention only recently. Previous work with (TBSV) in model host yeast has revealed essential roles for phosphatidylethanolamine and sterols in viral replication. To further our understanding of the role of sterols in tombusvirus replication, in this work we showed that the TBSV p33 and p92 replication proteins could bind to sterols The sterol binding by p33 is supported by cholesterol recognition/interaction amino acid consensus (CRAC) and CARC-like sequences within the two transmembrane domains of p33. Mutagenesis of the critical Y amino acids within the CRAC and CARC sequences blocked TBSV replication in yeast and plant cells. We also showed the enrichment of sterols in the detergent-resistant membrane (DRM) fractions obtained from yeast and plant cells replicating TBSV. The DRMs could support viral RNA synthesis on both the endogenous and exogenous templates. A lipidomic approach showed the lack of enhancement of sterol levels in yeast and plant cells replicating TBSV. The data support the notion that the TBSV replication proteins are associated with sterol-rich detergent-resistant membranes in yeast and plant cells. Together, the results obtained in this study and the previously published results support the local enrichment of sterols around the viral replication proteins that is critical for TBSV replication. One intriguing aspect of viral infections is their dependence on efficient subcellular assembly platforms serving replication, virion assembly, or virus egress via budding out of infected cells. These assembly platforms might involve sterol-rich membrane microdomains, which are heterogeneous and highly dynamic nanoscale structures usurped by various viruses. Here, we demonstrate that TBSV p33 and p92 replication proteins can bind to sterol Mutagenesis analysis of p33 within the CRAC and CARC sequences involved in sterol binding shows the important connection between the abilities of p33 to bind to sterol and to support TBSV replication in yeast and plant cells. Together, the results further strengthen the model that cellular sterols are essential as proviral lipids during viral replication.

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“…This discovery led to identification of the anti-tombusviral activities of additional TPR-domain proteins, such as Ttc4 oncogene-like Cns1p co-chaperone and the Hop/Sti1 co-chaperone, both of which bind to tombusvirus replication proteins (Lin and Nagy, 2013; Xu et al, 2014) and inhibit the p33/p92-driven recruitment of the TBSV RNA for replication and decrease the efficiency of VRC assembly (Lin et al, 2012). Thus, these co-chaperones with TPR-domains seem to act as direct CIRFs against tombusviruses.…”

Section: Characterization Of Antiviral Functions Of the Identified Cementioning

confidence: 99%

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

Cited by 24 publications

References 131 publications

HOP3, a member of the HOP family in Arabidopsis, interacts with BiP and plays a major role in the ER stress response

HOP3, a member of the HOP family in Arabidopsis, interacts with BiP and plays a major role in the ER stress response

Sterol Binding by the Tombusviral Replication Proteins Is Essential for Replication in Yeast and Plants

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

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