Transcription and RNA Replication of Tacaribe Virus Genome and Antigenome Analogs Require N and L Proteins: Z Protein Is an Inhibitor of These Processes

López, Nora; Jácamo, Rodrigo; Franze-Fernández, Marı́a T.

doi:10.1128/jvi.75.24.12241-12251.2001

Cited by 150 publications

(183 citation statements)

References 29 publications

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“…By using this system, we showed that Z is not required for RNA synthesis mediated by the LCMV polymerase (13), but, rather, Z exhibits a dose-dependent inhibitory effect on both LCMV transcription and RNA replication (7). Similar findings have been subsequently reported for the Z protein of Tacaribe virus (TV), a New World arenavirus (14).…”

Section: A Renaviruses Include Lassa Fever Virus (Lfv) and The Southsupporting

confidence: 75%

The small RING finger protein Z drives arenavirus budding: Implications for antiviral strategies

Perez

Craven

Torre

2003

Proc. Natl. Acad. Sci. U.S.A.

308

388

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By using a reverse genetics system that is based on the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), we have identified the arenavirus small RING finger Z protein as the main driving force of virus budding. Both LCMV and Lassa fever virus (LFV) Z proteins exhibited self-budding activity, and both substituted efficiently for the late domain that is present in the Gag protein of Rous sarcoma virus. LCMV and LFV Z proteins contain proline-rich motifs that are characteristic of late domains. Mutations in the PPPY motif of LCMV Z severely impaired the formation of virus-like particles. LFV Z contains two different proline-rich motifs, PPPY and PTAP, which are separated by eight amino acids. Mutational analysis revealed that both motifs are required for efficient LFV Z-mediated budding. Both LCMV and LFV Z proteins recruited to the plasma membrane Tsg101, which is a component of the class E vacuolar protein sorting machinery that has been implicated in budding of HIV and Ebola virus. A renaviruses include Lassa fever virus (LFV) and the South American hemorrhagic fever (HF) viruses. These viruses cause severe human disease, and they pose a threat as agents of bioterrorism (1). The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is an important model with which to study both acute and persistent viral infection (2). In addition, LCMV provides an excellent system with which to study basic aspects of the molecular and cell biology of HF arenaviruses.LCMV is an enveloped virus, whose genome consists of two negative-sense, single-stranded RNA segments, called L (7.2 kb) and S (3.4 kb). Each segment uses an ambisense coding organization to direct the synthesis of two gene products in opposite orientation, and each is separated by an intergenic region (3) The S RNA encodes the nucleoprotein (NP), and the two surface virion glycoproteins (GPs), GP-1 and GP-2, which are derived by proteolytic cleavage of a precursor polypeptide, GP-C (4). GP-1 and GP-2 form the spikes on the virion envelope and mediate cell entry by interaction with the host cell surface receptor (5). The L RNA directs the synthesis of the virus RNA-dependent RNA polymerase (L protein), and a small RING finger protein called Z (11 kDa) (6). The NP associates with the viral genomic RNA species and L to form the viral ribonucleoprotein (RNP) core that is competent in transcription and RNA replication, and constitutes the minimal infectious unit (7). The role of Z in the virus life cycle is poorly understood, and homologues of Z are not found in other negativestrand (NS) RNA viruses. Z is a structural component of the virus (8), and in infected cells, Z has been reported to interact with several cellular factors, including promyelocytic leukemia protein (9), and the eukaryotic translation initiation factor 4E, the latter of which has been proposed to repress CAP-dependent translation (10, 11). In addition, early studies suggested a role of Z in viral transcriptional regulation (12).We have developed a reverse genetic system f...

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Section: A Renaviruses Include Lassa Fever Virus (Lfv) and The Southsupporting

confidence: 75%

The small RING finger protein Z drives arenavirus budding: Implications for antiviral strategies

Perez

Craven

Torre

2003

Proc. Natl. Acad. Sci. U.S.A.

308

388

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“…Arenavirus genomic replication requires L and an appropriate NP-encapsidated RNA template (27,28). Although NP is not essential for the catalytic activity of L itself ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Arenavirus Z protein controls viral RNA synthesis by locking a polymerase–promoter complex

Kranzusch

Whelan

2011

Proc. Natl. Acad. Sci. U.S.A.

104

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Arenaviruses form a noncytolytic infection in their rodent hosts, yet can elicit severe hemorrhagic disease in humans. How arenaviruses regulate gene expression remains unclear, and further understanding may provide insight into the dichotomy of these disparate infection processes. Here we reconstitute arenavirus RNA synthesis initiation and gene expression regulation in vitro using purified components and demonstrate a direct role of the viral Z protein in controlling RNA synthesis. Our data reveal that Z forms a species-specific complex with the viral polymerase (L) and inhibits RNA synthesis initiation by impairing L catalytic activity. This Z-L complex locks the viral polymerase in a promoter-bound, catalytically inactive state and may additionally ensure polymerase packaging during virion maturation. Z modulates host factors involved in cellular translation, proliferation, and antiviral signaling. Our data defines an additional role in governing viral RNA synthesis, revealing Z as the center of a network of host and viral connections that regulates viral gene expression.transcription factor | Machupo virus | matrix protein | negative-strand RNA virus | gene regulation T ranscription initiation is a fundamental focal point of gene expression regulation in all orders of life. Modulation of RNA synthesis affords an important response to stress, alterations in growth conditions, and environmental cues. Although initiation of RNA synthesis is often indirectly controlled through gene promoters and accessory signaling elements, regulation also occurs through factors directly interacting with and altering the catalytic potential of the RNA synthesis machinery itself (1). Studies with phage T7 and the T7 lysozyme repressor system have provided an important paradigm for control of viral RNA transcription (2, 3), but these processes remain a mystery for many eukaryotic viruses and medically relevant pathogens. Gene expression regulation is particularly critical for negative-sense RNA viruses of the family Arenaviridae, which must respond to input from the host environment to maintain a noncytolytic infection in their rodent reservoir (4). In stark contrast to this persistent infection, arenavirus infection in humans can lead to severe hemorrhagic fever disease and many arenaviruses represent important emerging pathogens (5). Intriguingly, recent evidence indicates that the balance between persistent and acute viral infection can be altered by a single mutation within the viral polymerase (6). Mechanistic insight into how arenaviruses tune gene expression and control viral RNA synthesis is required to further our understanding of the response of arenavirus infection to various host and cellular environments.Arenaviruses are the simplest of all hemorrhagic fever viruses, with only four viral proteins. The viral genome consists of two segments of single-stranded negative-sense RNA, where each segment encodes two proteins in an ambisense orientation. The small segment encodes for the viral glycoprotein, essential for entr...

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“…LCMV is the prototype arenavirus; its genome includes two RNA segments, L and S, that use an ambisense strategy for gene expression. The L segment encodes the 90 amino acid Z protein, a zinc-finger protein implicated in budding (Pérez et al, 2003;Salvato et al, 1992), and the L protein, the RNA-dependent RNA polymerase, of 2210 amino acids (Fuller-Pace & Southern, 1989;Lee et al, 2000;Lopez et al, 2001;Singh et al, 1987). The S segment encodes the glycoprotein precursor (GP-C) and the nucleoprotein (NP) (Buchmeier et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

Martı́n

Abia

Domingo

et al. 2009

Journal of General Virology

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Previous studies have documented that, in the presence of the mutagenic base analogue 5-fluorouracil (FU), lymphocytic choriomeningitis virus (LCMV) that persisted in BHK-21 cells decreased its infectivity to a larger extent than intracellular viral RNA levels, prior to virus extinction. This observation, together with in silico simulations, led to the proposal of the lethal defection model of virus extinction. This model suggests the participation of defective-interfering genomes in the loss of infectivity by increased mutagenesis. Since LCMV naturally produces defective-interfering particles, it was important to show that a capacity to interfere is produced in association with FU treatment. Here, we document that BHK-21 cells persistently infected with LCMV grown in the presence of FU, but not in its absence, generated an interfering activity that suppressed LCMV infectivity. Interference was specific for LCMV and was sensitive to UV irradiation and its activity was dose-and time-dependent. The interfering preparations produced positive LCMV immunofluorescence and viral particles seen by electron microscopy when used to infect cells, despite some preparations being devoid of detectable infectivity. Interference did not involve significant increases of mutant spectrum complexity, as predicted by the lethal defection model. The results provide support for a specific interference associated with LCMV when the virus replicates in the presence of FU. The excess of interference relative to that observed in the absence of FU is necessary for LCMV extinction.

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Transcription and RNA Replication of Tacaribe Virus Genome and Antigenome Analogs Require N and L Proteins: Z Protein Is an Inhibitor of These Processes

Cited by 150 publications

References 29 publications

The small RING finger protein Z drives arenavirus budding: Implications for antiviral strategies

The small RING finger protein Z drives arenavirus budding: Implications for antiviral strategies

Arenavirus Z protein controls viral RNA synthesis by locking a polymerase–promoter complex

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

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