Rabies virus matrix protein regulates the balance of virus transcription and replication

Finke, Stefan; Mueller-Waldeck, Roland; Conzelmann, Karl‐Klaus

doi:10.1099/vir.0.19128-0

Cited by 138 publications

(122 citation statements)

References 42 publications

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“…5). Although the individual mechanisms remain undetermined, inhibition of viral RNA gene expression by overexpression of the matrix, or matrix-like, protein has been observed for influenza A virus and in a multitude of nonsegmented negative-sense RNA viral systems (38)(39)(40)(41). It is therefore possible that the Z-L-RNA complex and Z-L inhibition mechanism identified here may serve as an important paradigm for the link between transcription regulation and polymerase packaging of negative-sense RNA viruses.…”

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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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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“…7). This issue will have to be addressed in an additional study focusing on the contribution of the M protein to viral transcription and replication efficacies in detail, because it has been investigated previously for the related paramyxovirus rabies in a cell type different to moDCs (45).…”

Section: Discussionmentioning

confidence: 99%

Severe Impairment of Dendritic Cell Allostimulatory Activity by Sendai Virus Vectors Is Overcome by Matrix Protein Gene Deletion

Armeanu¹,

Bitzer²,

Smirnow³

et al. 2005

The Journal of Immunology

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Delivery of Ags to dendritic cells (DCs) plays a pivotal role in the induction of efficient immune responses ranging from immunity to tolerance. The observation that certain viral pathogens are able to infect DCs has led to a concept in which applications of recombinant viruses are used for Ag delivery with the potential benefit of inducing potent Ag-specific T cell responses directed against multiple epitopes. As a prerequisite for such an application, the infection of DCs by recombinant viruses should not interfere with their stimulatory capacity. In this context, we could show that an emerging negative-strand RNA viral vector system based on the Sendai virus (SeV) is able to efficiently infect monocyte-derived human DCs (moDCs). However, after infection with SeV wild type, both the response of DCs to bacterial LPS as a powerful mediator of DC maturation and the allostimulatory activity were severely impaired. Interestingly, using various recombinant SeV vectors that were devoid of single viral genes, we were able to identify the SeV matrix (M) protein as a key component in moDC functional impairment after viral infection. Consequently, use of M-deficient SeV vectors preserved the allostimulatory activity in infected moDCs despite an efficient expression of all other virally encoded genes, thereby identifying M-deficient vectors as a highly potent tool for the genetic manipulation of DCs.

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“…Such a role for M in viral transcription control has been described for other negative-stranded RNA viruses, such as vesicular stomatitis virus (VSV) and rabies virus (both members of the Rhabdoviridae family) (9,11,26,31,49) as well as for the influenza viruses (Orthomyxovirus family) (32,48). In addition, VSV-M has been implicated in the shutoff of cellular transcription (3,4), and rabies virus-M has been implicated in the stimulation of viral replication in vivo (14,15).…”

mentioning

confidence: 99%

Suppression of the Sendai Virus M Protein through a Novel Short Interfering RNA Approach Inhibits Viral Particle Production but Does Not Affect Viral RNA Synthesis

Mottet-Osman

Iseni

Pelet

et al. 2007

J Virol

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Short RNA interference is more and more widely recognized as an effective method to specifically suppress viral functions in eukaryotic cells. Here, we used an experimental system that allows suppression of the Sendai virus (SeV) M protein by using a target sequence, derived from the green fluorescent protein gene, that was introduced in the 3 untranslated region of the M protein mRNA. Silencing of the M protein gene was eventually achieved by a small interfering RNA (siRNA) directed against this target sequence. This siRNA was constitutively expressed in a cell line constructed by transduction with an appropriate lentivirus vector. Suppression of the M protein was sufficient to diminish virus production by 50-to 100-fold. This level of suppression had no apparent effect on viral replication and transcription, supporting the lack of M involvement in SeV transcription or replication control.Enveloped viruses derive their envelope from cellular membranes after the viral components have assembled at the lipid bilayer. The assembly process brings together the glycoproteins spanning the lipid bilayer with the inner core of the virus particle. The inner layer of the membrane generally contains a viral protein that bridges the glycoproteins and the inner core, dubbed the matrix or M protein. M is generally considered an essential protein, without which the production of virus particle production is highly impaired if not impossible.The M protein of Sendai virus (SeV-M), a member of the Paramyxovirinae subfamily, Paramyxoviridae family, is no exception to the rule. It is synthesized in the cytoplasm and self-associates to form a leaflet at the inner face of the plasma membrane (for a recent review, see reference 45). In the virus particle, it similarly carpets the inner part of the viral envelope, interacting with the two surface glycoproteins, HN and F, on the one hand and with the viral ribonucleoprotein complex (N protein plus viral RNA) associated with the L and P proteins on the other hand (for a review, see reference 29). In addition to its role in virus particle formation, paramyxovirus M has been reported to participate in the regulation of RNA synthesis (19,27,38,40,44). Such a role for M in viral transcription control has been described for other negative-stranded RNA viruses, such as vesicular stomatitis virus (VSV) and rabies virus (both members of the Rhabdoviridae family) (9,11,26,31,49) as well as for the influenza viruses (Orthomyxovirus family) (32, 48). In addition, VSV-M has been implicated in the shutoff of cellular transcription (3, 4), and rabies virus-M has been implicated in the stimulation of viral replication in vivo (14, 15).Our laboratory has long been interested in the SeV-M protein and, in particular, in its function in virus particle formation (13,35,36,43). To perform a structure-function analysis, one would ideally like to silence expression of the resident SeV-M gene and replace it with M mutants in a search for residues or domains that can modulate its functions. One approach would con...

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Rabies virus matrix protein regulates the balance of virus transcription and replication

Cited by 138 publications

References 42 publications

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

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

Severe Impairment of Dendritic Cell Allostimulatory Activity by Sendai Virus Vectors Is Overcome by Matrix Protein Gene Deletion

Suppression of the Sendai Virus M Protein through a Novel Short Interfering RNA Approach Inhibits Viral Particle Production but Does Not Affect Viral RNA Synthesis

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