Nucleolin/Nsr1p binds to the 3′ noncoding region of the tombusvirus RNA and inhibits replication

Jiang, Yi; Li, Zhenghe; Nagy, Peter D.

doi:10.1016/j.virol.2009.10.007

Cited by 30 publications

(39 citation statements)

References 53 publications

(118 reference statements)

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“…The differences in the mechanisms between CypA and Cpr7p were also substantial and included the following findings: (i) the domains involved in inhibition is the TPR domain in the case of Cpr7p and the cyclophilin domain in the case of CypA; (ii) also, CypA binds to the viral RNA, which seems to be important, while Cpr7p-driven inhibition is through binding to p33/p92 replication proteins; (iii) CypA becomes recruited to the VRC, while this has not yet been shown for Cpr7p. Those mechanistic features of CypA, which are based on RNA binding, are actually similar to the those for cellular nucleolin, which is also a restriction factor that inhibits the recruitment of viral (ϩ)RNA into replication through binding to viral (ϩ)RNA (49). Thus, it seems that different cellular restriction factors target similar early steps during tombusvirus replication.…”

Section: Discussionmentioning

confidence: 79%

“…The emerging picture from recent genome-wide screens and global proteomics approaches with tombusviruses indicates that many host proteins act as intrinsic restriction factors by inhibiting virus replication (28,32,44,49). Among the host restriction factors are cyclophilins, which are a large family of peptidyl-prolyl cis-trans isomerases with protein chaperone-like function.…”

Section: Discussionmentioning

confidence: 99%

“…Among the cellular restriction factors that have been characterized is nucleolin (Nsr1p in yeast), an RNA-binding protein that interferes with the recruitment of the viral RNA for replication (49). Additional restriction factors are the WW domain proteins, such as Rsp5p, a Nedd4 family E3 ubiquitin ligase, that regulate the degradation of p92 pol in yeast cells and inhibit the activity of VRCs in vitro (50,51).…”

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confidence: 99%

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

Kovalev

Nagy

2013

J Virol

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Replication of plus-stranded RNA viruses is greatly affected by numerous host-encoded proteins that act as restriction factors. Cyclophilins, which are a large family of cellular prolyl isomerases, have been found to inhibit Tomato bushy stunt tombusvirus (TBSV) replication in a Saccharomyces cerevisiae model based on genome-wide screens and global proteomics approaches. In this report, we further characterize single-domain cyclophilins, including the mammalian cyclophilin A and plant Roc1 and Roc2, which are orthologs of the yeast Cpr1p cyclophilin, a known inhibitor of TBSV replication in yeast. We found that recombinant CypA, Roc1, and Roc2 strongly inhibited TBSV replication in a cell-free replication assay. Additional in vitro studies revealed that CypA, Roc1, and Roc2 cyclophilins bound to the viral replication proteins, and CypA and Roc1 also bound to the viral RNA. These interactions led to inhibition of viral RNA recruitment, the assembly of the viral replicase complex, and viral RNA synthesis. A catalytically inactive mutant of CypA was also able to inhibit TBSV replication in vitro due to binding to the replication proteins and the viral RNA. Overexpression of CypA and its mutant in yeast or plant leaves led to inhibition of tombusvirus replication, confirming that CypA is a restriction factor for TBSV. Overall, the current work has revealed a regulatory role for the cytosolic single-domain Cpr1-like cyclophilins in RNA virus replication. Among the identified host factors, there are numerous inhibitory host proteins that serve as restriction factors for (ϩ)RNA viruses. However, the functions of the majority of these host proteins during (ϩ)RNA virus replication have not been fully revealed. The restriction factors likely interfere with the viral replication process, which takes place in membrane-bound viral replicase complexes (VRCs) in the cytoplasm of infected cells. The restriction factors potentially target the viral replication proteins, the viral RNA, or host-encoded proteins usurped by (ϩ)RNA viruses to aid the replication process (10-19).Recently, a major effort to dissect host restriction factors has been conducted with TBSV, which is a small (ϩ)RNA virus that is used as a model virus to study virus replication, recombination, and virus-host interactions, based on a yeast (Saccharomyces cerevisiae) model host (20-25). Genome-wide screens of yeast genes and global proteomics approaches have led to the identification of over 500 host genes/proteins that affect TBSV replication or recombination or interact with the viral replication proteins or viral RNA (1, 3, 24-32). Interestingly, ϳ25% of the identified factors seem to inhibit TBSV replication or recombination, suggesting that many host proteins might work as intrinsic restriction factors.The tombusvirus VRC consists of two viral replication proteins (p33 and p92 pol ) and ϳ10 host proteins (18,30,31,33). The auxiliary p33 replication protein is an RNA chaperone involved in recruitment of TBSV (ϩ)RNA to the site of replication, which is the c...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Kovalev

Nagy

2013

J Virol

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“…These interactions have been shown to mediate a number of different processes, including protein synthesis, RNA replication, release of virions, and trafficking of viral proteins (48)(49)(50)(51)(52)(53)(54). In addition, NCL has been shown to interact with the untranslated regions (UTR) of several other viruses, including tombusvirus, feline calicivirus, Norwalk virus, and poliovirus, where it may play roles in virus replication (55)(56)(57).…”

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confidence: 99%

Nucleolin Interacts with the Dengue Virus Capsid Protein and Plays a Role in Formation of Infectious Virus Particles

Balinsky

Schmeisser

Ganesan

et al. 2013

J Virol

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Dengue virus (DENV), a member of the genus Flavivirus, causes a spectrum of disease in humans that can range from a mild febrile illness to potentially fatal hemorrhage or shock syndromes. Four serotypes of DENV (DENV-1, -2, -3, and -4) are transmitted by the bite of a mosquito vector and are responsible for more than 50 million infections each year. Infection with one DENV serotype does not confer lasting immunity to the others (1-3). The most severe clinical manifestations of dengue are associated with secondary infections by a heterologous DENV serotype (2). Increasing urbanization, cocirculation of multiple DENV serotypes within the same geographic area, and expansion of its insect vector contribute to the increasing importance of dengue to global health (2, 3).DENV contains a positive-sense single-stranded RNA (ssRNA) genome that is translated as a single open reading frame. The resulting polyprotein is cleaved by virus and host proteases into three structural and at least seven nonstructural proteins (4, 5). The capsid (C) protein functions as a structural component of the DENV virion, encapsulating the ssRNA genome of the virus (4, 5). The DENV C protein is composed of four alpha helices with an unstructured amino terminus and forms antiparallel homodimers.

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“…Additional cellular cyclophilins, such as the CypA, and the related Ess1p parvulin also decrease TBSV RNA accumulation in yeast and plants (36,41,43). Moreover, the cellular nucleolin, an RNA-binding protein, inhibits TBSV replication by blocking the recruitment of the viral RNA into replication (44). Another group of cellular restriction factors is the WW motif-containing host proteins, such as Rsp5p Nedd4-like E3 ubiquitin ligase, which regulate the degradation of tombusviral p92 pol in yeast cells and inhibit the activity of VRC in vitro (45,46).…”

mentioning

confidence: 99%

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

Lin

Nagy

2014

J Virol

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Nucleolin/Nsr1p binds to the 3′ noncoding region of the tombusvirus RNA and inhibits replication

Cited by 30 publications

References 53 publications

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

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

Nucleolin Interacts with the Dengue Virus Capsid Protein and Plays a Role in Formation of Infectious Virus Particles

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

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