p38 and OGT Sequestration into Viral Inclusion Bodies in Cells Infected with Human Respiratory Syncytial Virus Suppresses MK2 Activities and Stress Granule Assembly

Fricke, Jens; Koo, Lily Y.; Brown, Charles R.; Collins, Peter L.

doi:10.1128/jvi.02263-12

Cited by 59 publications

(74 citation statements)

References 49 publications

(69 reference statements)

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“…According to this model, sequestration of O-linked N-acetylglucosamine transferase provides a mechanism for RSV to prevent stress granule assembly, since the modification of proteins with O-linked N-acetylglucosamine is an important early step in stress granule assembly (131). Sequestering host proteins in IBs to inhibit stress granule assembly is consistent with the negative correlation observed between the presence of large IBs and stress granule formation (128).…”

Section: Role Of Inclusion Bodies and Stress Granules In Rsv Infectionsupporting

confidence: 69%

“…The host proteins that colocalize with IBs include a number of antiviral, chaperone, and signaling proteins such as MAVS (124), MDA5 (124), phosphorylated p38 (128), O-linked N-acetylglucosamine transferase (128), and HSP70 (129). The presence of antiviral and signaling proteins within IBs opens up the possibility that these proteins are specifically sequestered within the inclusions to prevent host cell responses that would be unfavorable to RSV infection.…”

Section: Role Of Inclusion Bodies and Stress Granules In Rsv Infectionmentioning

confidence: 99%

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Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

2017

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SUMMARY Respiratory syncytial virus (RSV) infection is a significant cause of hospitalization of children in North America and one of the leading causes of death of infants less than 1 year of age worldwide, second only to malaria. Despite its global impact on human health, there are relatively few therapeutic options available to prevent or treat RSV infection. Paradoxically, there is a very large volume of information that is constantly being refined on RSV replication, the mechanisms of RSV-induced pathology, and community transmission. Compounding the burden of acute RSV infections is the exacerbation of preexisting chronic airway diseases and the chronic sequelae of RSV infection. A mechanistic link is even starting to emerge between asthma and those who suffer severe RSV infection early in childhood. In this article, we discuss developments in the understanding of RSV replication, pathogenesis, diagnostics, and therapeutics. We attempt to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.

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Section: Role Of Inclusion Bodies and Stress Granules In Rsv Infectionsupporting

confidence: 69%

Section: Role Of Inclusion Bodies and Stress Granules In Rsv Infectionmentioning

confidence: 99%

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

2017

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“…Marburg virus (MARV), another member of the filovirus family, recruits components of the endosomal complex required for transport (ESCRT) machinery to viral inclusions to enhance budding (80). The sequestration of cellular proteins within viral inclusions, including HuR and proteins involved in antiviral signaling, was also observed in respiratory syncytial virus (RSV) infection and dampened the antiviral host response (81)(82)(83). This supports the hypothesis that the sequestration of certain cellular proteins within viral inclusions promotes viral infection by disrupting antiviral signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions

Nelson

Schmidt

Deflubé

et al. 2016

J Virol

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A hallmark of Ebola virus (EBOV) infection is the formation of viral inclusions in the cytoplasm of infected cells. These viral in-clusions contain the EBOV nucleocapsids and are sites of viral replication and nucleocapsid maturation. Although there is growing evidence that viral inclusions create a protected environment that fosters EBOV replication, little is known about their role in the host response to infection. The cellular stress response is an effective antiviral strategy that leads to stress granule (SG) formation and translational arrest mediated by the phosphorylation of a translation initiation factor, the ␣ subunit of eukaryotic initiation factor 2 (eIF2␣). Here, we show that selected SG proteins are sequestered within EBOV inclusions, where they form distinct granules that colocalize with viral RNA. These inclusion-bound (IB) granules are functionally and structurally different from canonical SGs. Formation of IB granules does not indicate translational arrest in the infected cells. We further show that EBOV does not induce formation of canonical SGs or eIF2␣ phosphorylation at any time postinfection but is unable to fully inhibit SG formation induced by different exogenous stressors, including sodium arsenite, heat, and hippuristanol. Despite the sequestration of SG marker proteins into IB granules, canonical SGs are unable to form within inclusions, which we propose might be mediated by a novel function of VP35, which disrupts SG formation. This function is independent of VP35's RNA binding activity. Further studies aim to reveal the mechanism for SG protein sequestration and precise function within inclusions. IMPORTANCEAlthough progress has been made developing antiviral therapeutics and vaccines against the highly pathogenic Ebola virus (EBOV), the cellular mechanisms involved in EBOV infection are still largely unknown. To better understand these intracellular events, we investigated the cellular stress response, an antiviral pathway manipulated by many viruses. We show that EBOV does not induce formation of stress granules (SGs) in infected cells and is therefore unrestricted by their concomitant translational arrest. We identified SG proteins sequestered within viral inclusions, which did not impair protein translation. We further show that EBOV is unable to block SG formation triggered by exogenous stress early in infection. These findings provide insight into potential targets of therapeutic intervention. Additionally, we identified a novel function of the interferon antagonist VP35, which is able to disrupt SG formation.

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“…This indicated that M and F may interact at or near the IBs and implicated these structures in the cascade of late-stage events that lead to virions. IBs are multifunctional bodies (45,46) and are believed to represent the sites of viral replication. Coexpression of N and P is sufficient to induce formation of IBs (47).…”

mentioning

confidence: 99%

The Respiratory Syncytial Virus Phosphoprotein, Matrix Protein, and Fusion Protein Carboxy-Terminal Domain Drive Efficient Filamentous Virus-Like Particle Formation

Meshram

Baviskar

Ognibene

et al. 2016

J Virol

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Virus-like particles (VLPs) are attractive as a vaccine concept. For human respiratory syncytial virus (hRSV), VLP assembly is poorly understood and appears inefficient. Hence, hRSV antigens are often incorporated into foreign VLP systems to generate anti-RSV vaccine candidates. To better understand the assembly, and ultimately to enable efficient production, of authentic hRSV VLPs, we examined the associated requirements and mechanisms. In a previous analysis in HEp-2 cells, the nucleoprotein (N), phosphoprotein (P), matrix protein (M), and fusion protein (F) were required for formation of filamentous VLPs, which, similar to those of wild-type virus, were associated with the cell surface. Using fluorescence and electron microscopy combined with immunogold labeling, we examined the surfaces of transfected HEp-2 cells and further dissected the process of filamentous VLP formation. Our results show that N is not required. Coexpression of P plus M plus F, but not P plus M, M plus F, or P plus F, induced both viral protein coalescence and formation of filamentous VLPs that resembled wild-type virions. Despite suboptimal coalescence in the absence of P, the M and F proteins, when coexpressed, formed cell surface-associated filaments with abnormal morphology, appearing longer and thinner than wild-type virions. For F, only the carboxy terminus (Fstem) was required, and addition of foreign protein sequences to Fstem allowed incorporation into VLPs. Together, the data show that P, M, and the F carboxy terminus are sufficient for robust viral protein coalescence and filamentous VLP formation and suggest that M-F interaction drives viral filament formation, with P acting as a type of cofactor facilitating the process and exerting control over particle morphology. IMPORTANCEhRSV is responsible for >100,000 deaths in children worldwide, and a vaccine is not available. Among the potential anti-hRSV approaches are virus-like particle (VLP) vaccines, which, based on resemblance to virus or viral components, can induce protective immunity. For hRSV, few reports are available concerning authentic VLP production or testing, in large part because VLP production is inefficient and the mechanisms underlying particle assembly are poorly understood. Here, we took advantage of the cell-associated nature of RSV particles and used high-resolution microscopy analyses to examine the viral proteins required for formation of wild-type-virus-resembling VLPs, the contributions of these proteins to morphology, and the domains involved in incorporation of the antigenically important viral F protein. The results provide new insights that will facilitate future production of hRSV VLPs with defined shapes and compositions and may translate into improved manufacture of live-attenuated hRSV vaccines. H uman respiratory syncytial virus (hRSV) is an important viral agent of respiratory tract disease in infants, children, immunosuppressed individuals, and the elderly (1-3). In pursuit of a vaccine to prevent hRSV disease, a virus-like particle (...

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p38 and OGT Sequestration into Viral Inclusion Bodies in Cells Infected with Human Respiratory Syncytial Virus Suppresses MK2 Activities and Stress Granule Assembly

Cited by 59 publications

References 49 publications

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions

The Respiratory Syncytial Virus Phosphoprotein, Matrix Protein, and Fusion Protein Carboxy-Terminal Domain Drive Efficient Filamentous Virus-Like Particle Formation

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