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Picornaviruses and nuclear functions: targeting a cellular compartment distinct from the replication site of a positive-strand RNA virus.

Flather D, Semler BL - Front Microbiol (2015)

Bottom Line: As a result of the limited coding capacity of these viruses, cellular proteins are required by these intracellular parasites for both translation and genomic RNA replication.As a result, picornaviruses disrupt nucleocytoplasmic trafficking to exploit protein functions normally localized to a different cellular compartment from which they translate their genome to facilitate efficient replication.The interactions of picornavirus proteins and host-cell nuclei are extensive, required for a productive infection, and are the focus of this review.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Center for Virus Research, School of Medicine, University of California, Irvine Irvine, CA, USA.

ABSTRACT
The compartmentalization of DNA replication and gene transcription in the nucleus and protein production in the cytoplasm is a defining feature of eukaryotic cells. The nucleus functions to maintain the integrity of the nuclear genome of the cell and to control gene expression based on intracellular and environmental signals received through the cytoplasm. The spatial separation of the major processes that lead to the expression of protein-coding genes establishes the necessity of a transport network to allow biomolecules to translocate between these two regions of the cell. The nucleocytoplasmic transport network is therefore essential for regulating normal cellular functioning. The Picornaviridae virus family is one of many viral families that disrupt the nucleocytoplasmic trafficking of cells to promote viral replication. Picornaviruses contain positive-sense, single-stranded RNA genomes and replicate in the cytoplasm of infected cells. As a result of the limited coding capacity of these viruses, cellular proteins are required by these intracellular parasites for both translation and genomic RNA replication. Being of messenger RNA polarity, a picornavirus genome can immediately be translated upon entering the cell cytoplasm. However, the replication of viral RNA requires the activity of RNA-binding proteins, many of which function in host gene expression, and are consequently localized to the nucleus. As a result, picornaviruses disrupt nucleocytoplasmic trafficking to exploit protein functions normally localized to a different cellular compartment from which they translate their genome to facilitate efficient replication. Furthermore, picornavirus proteins are also known to enter the nucleus of infected cells to limit host-cell transcription and down-regulate innate antiviral responses. The interactions of picornavirus proteins and host-cell nuclei are extensive, required for a productive infection, and are the focus of this review.

No MeSH data available.


Related in: MedlinePlus

Ribonucleoproteins (RNPs) comprised of nuclear-resident proteins facilitate enterovirus RNA replication. (A) Nuclear-resident proteins PCBP2 (dark blue) and PABP1 (green) act in conjunction with viral protein 3CD (fuchsia) to circularize genomic RNA for use as templates to produce negative-sense RNA intermediates. (B) Nuclear protein hnRNP C1/C2 (light blue) interacts with both termini of negative-sense RNA molecules and is hypothesized to circularize the negative-sense template to promote genomic RNA production. Although likely in the form of double-stranded RNA, the negative-sense RNA is shown here as single stranded for clarity. Viral protein 2C (purple) interacts with the 5′-terminus of negative-sense RNA, although the direct function of this protein in viral RNA replication is unclear. The viral RNA-dependent RNA polymerase 3Dpol (brown) is recruited to these circularized templates and initiates viral RNA synthesis. VPg (yellow), the viral protein that primes RNA synthesis, is found on RNA molecules that have not been translated.
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Figure 4: Ribonucleoproteins (RNPs) comprised of nuclear-resident proteins facilitate enterovirus RNA replication. (A) Nuclear-resident proteins PCBP2 (dark blue) and PABP1 (green) act in conjunction with viral protein 3CD (fuchsia) to circularize genomic RNA for use as templates to produce negative-sense RNA intermediates. (B) Nuclear protein hnRNP C1/C2 (light blue) interacts with both termini of negative-sense RNA molecules and is hypothesized to circularize the negative-sense template to promote genomic RNA production. Although likely in the form of double-stranded RNA, the negative-sense RNA is shown here as single stranded for clarity. Viral protein 2C (purple) interacts with the 5′-terminus of negative-sense RNA, although the direct function of this protein in viral RNA replication is unclear. The viral RNA-dependent RNA polymerase 3Dpol (brown) is recruited to these circularized templates and initiates viral RNA synthesis. VPg (yellow), the viral protein that primes RNA synthesis, is found on RNA molecules that have not been translated.

Mentions: The 5′ non-coding regions of picornavirus genomes contain RNA structural elements that are required for the replication of these genomes by acting as scaffolds for protein interactions (Andino et al., 1990; Barton et al., 2001; Nateri et al., 2002; Nagashima et al., 2008). Electrophoretic mobility shift assays incorporating recombinant proteins and subgenomic portions of poliovirus RNA molecules have been instrumental in identifying the components of RNP elements in vitro, that may be important for the process of enterovirus RNA replication. The 5′ terminal structure of the poliovirus genome, known as S-L I or cloverleaf, has been shown to be critical for the formation of RNP complexes that function in the initiation of RNA synthesis (Andino et al., 1993). One of the proteins involved in this RNP formation is the nuclear-resident PCBP2, which binds to the S-L I structure with increased affinity when the viral polymerase precursor, 3CD, is also present near the 5′-terminus of the RNA, forming a ternary complex (Gamarnik and Andino, 1997, 2000; Parsley et al., 1997). On the opposite terminus of the genome, PABP1 associates with the genetically encoded poly(A) tract of the poliovirus genome. Through co-immunoprecipitation using antibodies directed against PABP1, it has been demonstrated that 3CD and PABP1 directly interact in poliovirus-infected cells. As a result, it has been proposed that PABP1 acts as a bridge to link both ends of the viral genome because it is able to simultaneously interact with the 3′-terminus of poliovirus genomic RNA as well as both 3CD and PCBP2, which are present on the 5′-terminus of the same RNA molecule (Herold and Andino, 2001). More recently it has been shown that PCBP2 binds to both the S-L I structure and to a C-rich spacer region that is found between S-L I and the IRES element (Toyoda et al., 2007). Based on similar interactions between PCBP2 and CVB3 RNA, it is likely that PCBP2 modulates the RNA replication of this closely related virus, and the poly(C) binding protein hnRNP K may be exploited in place of PCBP2 by EV71 (Lin et al., 2008; Zell et al., 2008a,b) (Figure 4A).


Picornaviruses and nuclear functions: targeting a cellular compartment distinct from the replication site of a positive-strand RNA virus.

Flather D, Semler BL - Front Microbiol (2015)

Ribonucleoproteins (RNPs) comprised of nuclear-resident proteins facilitate enterovirus RNA replication. (A) Nuclear-resident proteins PCBP2 (dark blue) and PABP1 (green) act in conjunction with viral protein 3CD (fuchsia) to circularize genomic RNA for use as templates to produce negative-sense RNA intermediates. (B) Nuclear protein hnRNP C1/C2 (light blue) interacts with both termini of negative-sense RNA molecules and is hypothesized to circularize the negative-sense template to promote genomic RNA production. Although likely in the form of double-stranded RNA, the negative-sense RNA is shown here as single stranded for clarity. Viral protein 2C (purple) interacts with the 5′-terminus of negative-sense RNA, although the direct function of this protein in viral RNA replication is unclear. The viral RNA-dependent RNA polymerase 3Dpol (brown) is recruited to these circularized templates and initiates viral RNA synthesis. VPg (yellow), the viral protein that primes RNA synthesis, is found on RNA molecules that have not been translated.
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Related In: Results  -  Collection

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Show All Figures
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Figure 4: Ribonucleoproteins (RNPs) comprised of nuclear-resident proteins facilitate enterovirus RNA replication. (A) Nuclear-resident proteins PCBP2 (dark blue) and PABP1 (green) act in conjunction with viral protein 3CD (fuchsia) to circularize genomic RNA for use as templates to produce negative-sense RNA intermediates. (B) Nuclear protein hnRNP C1/C2 (light blue) interacts with both termini of negative-sense RNA molecules and is hypothesized to circularize the negative-sense template to promote genomic RNA production. Although likely in the form of double-stranded RNA, the negative-sense RNA is shown here as single stranded for clarity. Viral protein 2C (purple) interacts with the 5′-terminus of negative-sense RNA, although the direct function of this protein in viral RNA replication is unclear. The viral RNA-dependent RNA polymerase 3Dpol (brown) is recruited to these circularized templates and initiates viral RNA synthesis. VPg (yellow), the viral protein that primes RNA synthesis, is found on RNA molecules that have not been translated.
Mentions: The 5′ non-coding regions of picornavirus genomes contain RNA structural elements that are required for the replication of these genomes by acting as scaffolds for protein interactions (Andino et al., 1990; Barton et al., 2001; Nateri et al., 2002; Nagashima et al., 2008). Electrophoretic mobility shift assays incorporating recombinant proteins and subgenomic portions of poliovirus RNA molecules have been instrumental in identifying the components of RNP elements in vitro, that may be important for the process of enterovirus RNA replication. The 5′ terminal structure of the poliovirus genome, known as S-L I or cloverleaf, has been shown to be critical for the formation of RNP complexes that function in the initiation of RNA synthesis (Andino et al., 1993). One of the proteins involved in this RNP formation is the nuclear-resident PCBP2, which binds to the S-L I structure with increased affinity when the viral polymerase precursor, 3CD, is also present near the 5′-terminus of the RNA, forming a ternary complex (Gamarnik and Andino, 1997, 2000; Parsley et al., 1997). On the opposite terminus of the genome, PABP1 associates with the genetically encoded poly(A) tract of the poliovirus genome. Through co-immunoprecipitation using antibodies directed against PABP1, it has been demonstrated that 3CD and PABP1 directly interact in poliovirus-infected cells. As a result, it has been proposed that PABP1 acts as a bridge to link both ends of the viral genome because it is able to simultaneously interact with the 3′-terminus of poliovirus genomic RNA as well as both 3CD and PCBP2, which are present on the 5′-terminus of the same RNA molecule (Herold and Andino, 2001). More recently it has been shown that PCBP2 binds to both the S-L I structure and to a C-rich spacer region that is found between S-L I and the IRES element (Toyoda et al., 2007). Based on similar interactions between PCBP2 and CVB3 RNA, it is likely that PCBP2 modulates the RNA replication of this closely related virus, and the poly(C) binding protein hnRNP K may be exploited in place of PCBP2 by EV71 (Lin et al., 2008; Zell et al., 2008a,b) (Figure 4A).

Bottom Line: As a result of the limited coding capacity of these viruses, cellular proteins are required by these intracellular parasites for both translation and genomic RNA replication.As a result, picornaviruses disrupt nucleocytoplasmic trafficking to exploit protein functions normally localized to a different cellular compartment from which they translate their genome to facilitate efficient replication.The interactions of picornavirus proteins and host-cell nuclei are extensive, required for a productive infection, and are the focus of this review.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Center for Virus Research, School of Medicine, University of California, Irvine Irvine, CA, USA.

ABSTRACT
The compartmentalization of DNA replication and gene transcription in the nucleus and protein production in the cytoplasm is a defining feature of eukaryotic cells. The nucleus functions to maintain the integrity of the nuclear genome of the cell and to control gene expression based on intracellular and environmental signals received through the cytoplasm. The spatial separation of the major processes that lead to the expression of protein-coding genes establishes the necessity of a transport network to allow biomolecules to translocate between these two regions of the cell. The nucleocytoplasmic transport network is therefore essential for regulating normal cellular functioning. The Picornaviridae virus family is one of many viral families that disrupt the nucleocytoplasmic trafficking of cells to promote viral replication. Picornaviruses contain positive-sense, single-stranded RNA genomes and replicate in the cytoplasm of infected cells. As a result of the limited coding capacity of these viruses, cellular proteins are required by these intracellular parasites for both translation and genomic RNA replication. Being of messenger RNA polarity, a picornavirus genome can immediately be translated upon entering the cell cytoplasm. However, the replication of viral RNA requires the activity of RNA-binding proteins, many of which function in host gene expression, and are consequently localized to the nucleus. As a result, picornaviruses disrupt nucleocytoplasmic trafficking to exploit protein functions normally localized to a different cellular compartment from which they translate their genome to facilitate efficient replication. Furthermore, picornavirus proteins are also known to enter the nucleus of infected cells to limit host-cell transcription and down-regulate innate antiviral responses. The interactions of picornavirus proteins and host-cell nuclei are extensive, required for a productive infection, and are the focus of this review.

No MeSH data available.


Related in: MedlinePlus