Molecular Biology of the Prototype Arenavirus, Lymphocytic Choriomeningitis Virus

Salvato, María S.

doi:10.1007/978-1-4615-3028-2_8

Cited by 38 publications

(31 citation statements)

References 73 publications

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“…In both S and L RNAs, the genes are arranged in opposite orientations and are separated by noncoding sequences that have the potential to form stable secondary structures (14). S and L genomes and antigenomes are found only as nucleocapsids tightly bound to N protein, and the coding sequences are expressed from mRNAs transcribed from the 3Ј region of the genomes and antigenomes (1,14,20,27). These mRNAs end within the intergenic region and contain short stretches of nontemplated nucleotides at their 5Ј ends, which are capped (20,21).…”

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confidence: 99%

Mapping of the Tacaribe Arenavirus Z-Protein Binding Sites on the L Protein Identified both Amino Acids within the Putative Polymerase Domain and a Region at the N Terminus of L That Are Critically Involved in Binding

Wilda

López

Casabona

et al. 2008

J Virol

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Tacaribe virus (TacV) is the prototype of the New World group of arenaviruses. The TacV genome encodes four proteins: the nucleoprotein (N), the glycoprotein precursor, the polymerase (L), and a RING finger protein (Z). Using a reverse genetics system, we demonstrated that TacV N and L are sufficient to drive transcription and replication mediated by TacV In the present study, we mapped the TacV Z-binding sites on the 2,210-amino-acid L polymerase. To that end, we performed deletion analysis and point mutations of L and studied the Z-L interaction by coimmunoprecipitation with specific sera. We found that the C-terminal region of L was not essential for the interaction and identified two noncontiguous regions that were critical for binding: one at the N-terminus of L between residues 156 and 292 and a second one in the polymerase domain (domain III). The importance of domain III in binding was revealed by substitutions in D1188 and H1189 within motif A and in each residue of the conserved SDD sequence (residues 1328, 1329, and 1330) within motif C. Our results showed that of the substituted residues, only H1189 and D1329 appeared to be critically involved in binding Z.Tacaribe virus (TacV) is the prototype of the New World group of arenaviruses. Within this group, the viruses form three phylogenetically distinct clades, one of which includes TacV together with the known South American pathogens that produce severe hemorrhagic disease: the Junin, Machupo, Guanarito, and Sabia viruses and the recently described Chapare virus (4, 7, 11). TacV, however, seems not to be a human pathogen.TacV is an enveloped virus containing two single-stranded RNA segments called S and L. The S RNA contains two genes encoding respectively the nucleoprotein (N [64 kDa]) and the glycoprotein precursor (55 kDa) of the surface glycoproteins (13). The L RNA encodes the RNA-dependent RNA polymerase (RdRp) (L protein [240 kDa]) (16) and a small protein with a RING finger motif, called Z (11 kDa) (17). In both S and L RNAs, the genes are arranged in opposite orientations and are separated by noncoding sequences that have the potential to form stable secondary structures (14). S and L genomes and antigenomes are found only as nucleocapsids tightly bound to N protein, and the coding sequences are expressed from mRNAs transcribed from the 3Ј region of the genomes and antigenomes (1,14,20,27). These mRNAs end within the intergenic region and contain short stretches of nontemplated nucleotides at their 5Ј ends, which are capped (20,21).Using a reconstituted transcription and replication system based on plasmid-supplied TacV RNAs and proteins, we demonstrated that L and N are the only viral proteins required for full-cycle RNA replication and transcription (22), for a faithful initiation of both processes, and for correct termination of mRNA transcription (21). Using this system, we also demonstrated that TacV Z protein is a potent inhibitor of both viral RNA replication and transcription (22). Lymphocytic choriomeningitis virus (LCMV) Z protein e...

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Mapping of the Tacaribe Arenavirus Z-Protein Binding Sites on the L Protein Identified both Amino Acids within the Putative Polymerase Domain and a Region at the N Terminus of L That Are Critically Involved in Binding

Wilda

López

Casabona

et al. 2008

J Virol

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“…The arenavirus replication complex contains the viral genomic single-stranded RNA segments, nucleocapsid protein (NP), an RNA-dependent RNA polymerase (RdRp or L protein), and a small zinc-binding protein (Z) (17). Cellular proteins are also involved in viral replication (3,4,12).…”

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Role of the Promyelocytic Leukemia Protein PML in the Interferon Sensitivity of Lymphocytic Choriomeningitis Virus

Djavani

Rodas

Lukashevich

et al. 2001

J Virol

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Lymphocytic choriomeningitis virus (LCMV) induces type I interferon (alpha and beta interferon [IFN-␣ and IFN-␤]) upon infection and yet is sensitive to the addition of type II interferon (gamma interferon[Arenaviruses can replicate without significantly impacting the host or causing cytopathic effects. The arenavirus replication complex contains the viral genomic single-stranded RNA segments, nucleocapsid protein (NP), an RNA-dependent RNA polymerase (RdRp or L protein), and a small zinc-binding protein (Z) (17). Cellular proteins are also involved in viral replication (3,4,12). Here we describe the inhibitory influence of the promyelocytic leukemia protein (PML) that coprecipitates and colocalizes with cell-associated arenavirus complexes (2). PML is an oncoprotein that is expressed primarily in myeloid, epithelial, and endothelial cells, all infectable by arenaviruses and important in the pathogenesis of arenaviral hemorrhagic fevers. PML is induced by the alpha/beta interferons (IFN-␣/␤) acting on the ISRE and GAS promoter response elements (5,13,20). Interferons IFN-␣ and IFN-␤ are produced by many cell types upon viral infection, and IFN-␥ is produced in T lymphocytes or natural killer cells in response to antigens (16). IFNs are known for their inhibitory effects on cellular proliferation, and PML, as an effector of this function, is capable of suppressing cell proliferation (11,22,24).IFNs are also known for their antiviral effects. There are 50 to 100 IFN-inducible genes and several of them have antiviral activity, e.g., the p68 protein kinase, the 2Ј,5Ј-oligoadenylate synthetase (OAS), and certain Mx family proteins (19,20,23). The IFN-inducible PML has also recently been shown to have antiviral activity. In the absence of IFN, overexpression of PML diminishes infection by vesicular stomatitis virus (VSV) and influenza A virus, without affecting infection by encephalomyocarditis virus (EMCV), a virus known to be IFN resistant (6).Coimmunoprecipitation studies show specific interaction between PML and Z proteins of LCMV and Lassa fever virus, a related arenavirus. Genetically engineered mutations in PML were used to show that the Z protein binds the N-terminal region of PML, and this domain of PML, unlike the PML RING or the nuclear localization signal, is essential for colocalization of Z and PML (2). The work presented here demonstrates that PML expression diminishes LCMV expression, possibly through its interaction with the LCMV Z protein.PML and LCMV affect proliferation of MEF. The effects of PML expression on cell proliferation were examined in earlypassage mouse embryonic fibroblasts (MEFs) (22; this study). Fibroblasts lacking PML (PML Ϫ/Ϫ) grew faster and achieved higher cell densities than wild-type (PML ϩ/ϩ) cells and yet their cultures were morphologically indistinguishable. IFN treatment, which increases PML expression, reduces cell growth rates even more in both PML ϩ/ϩ and Ϫ/Ϫ fibroblasts. Infection with LCMV shortens the life of both MEF cultures approximately twofold (P Ͻ 0.05) (Fig. 1)...

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“…The L segment (7n2 kb) encodes the viral RNAdependent RNA polymerase (RdRp or L protein) on the genome-complementary strand and an 11 kDa ring-finger protein (Z) on the genomic strand. Both of these proteins are involved in regulation of transcription and replication processes and one or both may be implicated in the pathogenic potential of the virus (Salvato, 1993).…”

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The Lassa fever virus L gene: nucleotide sequence, comparison, and precipitation of a predicted 250 kDa protein with monospecific antiserum.

Lukashevich¹,

Djavani²,

Shapiro³

et al. 1997

Journal of General Virology

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Molecular Biology of the Prototype Arenavirus, Lymphocytic Choriomeningitis Virus

Cited by 38 publications

References 73 publications

Mapping of the Tacaribe Arenavirus Z-Protein Binding Sites on the L Protein Identified both Amino Acids within the Putative Polymerase Domain and a Region at the N Terminus of L That Are Critically Involved in Binding

Mapping of the Tacaribe Arenavirus Z-Protein Binding Sites on the L Protein Identified both Amino Acids within the Putative Polymerase Domain and a Region at the N Terminus of L That Are Critically Involved in Binding

Role of the Promyelocytic Leukemia Protein PML in the Interferon Sensitivity of Lymphocytic Choriomeningitis Virus

The Lassa fever virus L gene: nucleotide sequence, comparison, and precipitation of a predicted 250 kDa protein with monospecific antiserum.

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