Central role of the respiratory syncytial virus matrix protein in infection

Ghildyal, Reena; Ho, Adeline; Jans, David A.

doi:10.1111/j.1574-6976.2006.00025.x

Cited by 87 publications

(96 citation statements)

References 99 publications

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“…1, lane 3) and wt HRSV-infected cells (Fig. 1, lane 1), anti-M antibodies identified a protein of ϳ27 to 28 kDa, consistent with data from previous reports (19,52). No obvious difference in molecular mass was observed between M expressed alone and in the context of a viral infection.…”

Section: Resultssupporting

confidence: 79%

“…The roles of M in the viral assembly process likely include a function in bringing together the RNP and the viral envelope, since an M-containing sheath was revealed when the lipid membrane was removed from HRSV-induced surface filaments (1,27). In HRSV-infected cells, the M protein is first detected in the cytoplasm and nucleus (19). The purpose of nuclear targeting is not well understood but may be to inhibit host cell transcription or to temporarily divert M away from sites of viral transcription, which it was shown to inhibit (18,21).…”

mentioning

confidence: 99%

“…F also appears to play a role in viral attachment, and nucleolin was recently identified as a cellular receptor for the F protein (57). M is a nonglycosylated phosphorylated protein of 256 amino acids and a structural component of the HRSV virion (19,27,52). M is thought, in part by analogy to the role of matrix proteins in other virus systems, to play a key role in virion assembly by inhibiting viral transcription and by forming a bridge between the viral ribonucleoprotein (RNP) and envelope (13,21,25,27,54,56).…”

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confidence: 99%

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The Human Respiratory Syncytial Virus Matrix Protein Is Required for Maturation of Viral Filaments

Mitra

Baviskar

Duncan-Decocq

et al. 2012

J Virol

110

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An experimental system was developed to generate infectious human respiratory syncytial virus (HRSV) lacking matrix (M) protein expression (M-null virus) from cDNA. The role of the M protein in virus assembly was then examined by infecting HEp-2 and Vero cells with the M-null virus and assessing the impact on infectious virus production and viral protein trafficking. In the absence of M, the production of infectious progeny was strongly impaired. Immunofluorescence (IF) microscopy analysis using antibodies against the nucleoprotein (N), attachment protein (G), and fusion protein (F) failed to detect the characteristic virusinduced cell surface filaments, which are believed to represent infectious virions. In addition, a large proportion of the N protein was detected in viral replication factories termed inclusion bodies (IBs). High-resolution analysis of the surface of M-null virusinfected cells by field emission scanning electron microscopy (SEM) revealed the presence of large areas with densely packed, uniformly short filaments. Although unusually short, these filaments were otherwise similar to those induced by an M-containing control virus, including the presence of the viral G and F proteins. The abundance of the short, stunted filaments in the absence of M indicates that M is not required for the initial stages of filament formation but plays an important role in the maturation or elongation of these structures. In addition, the absence of mature viral filaments and the simultaneous increase in the level of the N protein within IBs suggest that the M protein is involved in the transport of viral ribonucleoprotein (RNP) complexes from cytoplasmic IBs to sites of budding.

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Section: Resultssupporting

confidence: 79%

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confidence: 99%

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confidence: 99%

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The Human Respiratory Syncytial Virus Matrix Protein Is Required for Maturation of Viral Filaments

Mitra

Baviskar

Duncan-Decocq

et al. 2012

J Virol

110

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“…This may be mediated in part by the viral matrix protein M that promotes p53 and p21 accumulation and decreases phosphorylation of the retinoblastoma protein (Rb) [66]. The ability of the M protein to traffic to the nucleus [67,68] may underlie this proviral effect. In addition to the M protein, recent studies have revealed that NS1 itself may also promote cell cycle arrest [69], which likely facilitates its IFNsuppressive function.…”

Section: Figurementioning

confidence: 99%

Viral degradasome hijacks mitochondria to suppress innate immunity

et al. 2013

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The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named "NS-degradasome" (NSD). The NSD is roughly ~300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity.

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“…The minimal RSV protein requirement for filament formation and budding of virus-like particles (VLPs) is F, N, P, and M (11,12). M, a key structural protein, directs assembly and budding on the plasma membrane, presumably by interacting with the cytoplasmic tails of the glycoproteins and with the RNP complex in the cytoplasm (7,(13)(14)(15). At the start of RSV assembly, M localizes into viral IBs (5,16).…”

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confidence: 99%

Dimerization of Matrix Protein Is Required for Budding of Respiratory Syncytial Virus

Förster

Maertens

Farrell

et al. 2015

J Virol

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Respiratory syncytial virus (RSV) infects epithelial cells of the respiratory tract and is a major cause of bronchiolitis and pneumonia in children and the elderly. The virus assembles and buds through the plasma membrane, forming elongated membrane filaments, but details of how this happens remain obscure. Oligomerization of the matrix protein (M) is a key step in the process of assembly and infectious virus production. In addition, it was suggested to affect the conformation of the fusion protein, the major current target for RSV antivirals, in the mature virus. The structure and assembly of M are thus key parameters in the RSV antiviral development strategy. The structure of RSV M was previously published as a monomer. Other paramyxovirus M proteins have been shown to dimerize, and biochemical data suggest that RSV M also dimerizes. Here, using size exclusion chromatography-multiangle laser light scattering, we show that the protein is dimeric in solution. We also crystallized M in two crystal forms and show that it assembles into equivalent dimers in both lattices. Dimerization interface mutations destabilize the M dimer in vitro. To assess the biological relevance of dimerization, we used confocal imaging to show that dimerization interface mutants of M fail to assemble into viral filaments on the plasma membrane. Additionally, budding and release of virus-like particles are prevented in M mutants that fail to form filaments. Importantly, we show that M is biologically active as a dimer and that the switch from M dimers to higher-order oligomers triggers viral filament assembly and virus production. IMPORTANCEHuman respiratory syncytial virus (RSV) is the most frequent cause of infantile bronchiolitis and pneumonia. The enormous burden of RSV makes it a major unmet target for a vaccine and antiviral drug therapy. Oligomerization of the matrix protein is a key step in the process of assembly and production of infectious virus, but the molecular mechanism of RSV assembly is still poorly understood. Here we show that the RSV matrix protein forms dimers in solution and in crystals; the dimer is essential for formation of higher-order oligomers. Destabilizing the dimer interface resulted in the loss of RSV filament formation and a lack of budding of virus-like particles. Importantly, our findings can potentially lead to new structure-based RSV inhibitors targeting the assembly process.H uman respiratory syncytial virus (RSV), an enveloped, nonsegmented negative-strand RNA paramyxovirus, is the major worldwide cause of bronchiolitis and pneumonia in infants and of morbidity and mortality in the elderly. Despite the large global impact of RSV infection, no specific antivirals or licensed vaccine is yet available (1, 2). Designing new antivirals requires detailed molecular and structural understanding of key steps in RSV replication.RSV encodes 11 proteins, with the 3 glycoproteins, the fusion protein (F), glycoprotein (G), and small hydrophobic protein (SH), being present in the viral envelope. The virion ...

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Central role of the respiratory syncytial virus matrix protein in infection

Cited by 87 publications

References 99 publications

The Human Respiratory Syncytial Virus Matrix Protein Is Required for Maturation of Viral Filaments

The Human Respiratory Syncytial Virus Matrix Protein Is Required for Maturation of Viral Filaments

Viral degradasome hijacks mitochondria to suppress innate immunity

Dimerization of Matrix Protein Is Required for Budding of Respiratory Syncytial Virus

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