Budding Capability of the Influenza Virus Neuraminidase Can Be Modulated by Tetherin

Yondola, Mark A.; Fernandes, Fiona; Belicha-Villanueva, Alan; Uccelini, Melissa; Gao, Qinshan; Carter, Carol; Palese, Peter

doi:10.1128/jvi.02188-10

Cited by 86 publications

(102 citation statements)

References 67 publications

(70 reference statements)

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“…In this study, we prove that the glycosites in the stalk domain of NA are glycosylated to regulate the activity, affinity, and specificity of NA to modulate IAV replication, suggesting that the glycans in the stalk domain of NA play an important role in the virulence and transmission of IAV. However, the relationship between NA activity and the diversity of the stalk domain, and whether the virus release is regulated by the glycosylation in the stalk domain is still unknown (24,25). Our study here revealed that NA glycosylation is important for IAV virulence and transmission.…”

Section: Discussionmentioning

confidence: 62%

Influenza A surface glycosylation and vaccine design

Lin

Tsai

et al. 2016

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

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We have shown that glycosylation of influenza A virus (IAV) hemagglutinin (HA), especially at position N-27, is crucial for HA folding and virus survival. However, it is not known whether the glycosylation of HA and the other two major IAV surface glycoproteins, neuraminidase (NA) and M2 ion channel, is essential for the replication of IAV. Here, we show that glycosylation of HA at N-142 modulates virus infectivity and host immune response. Glycosylation of NA in the stalk region affects its structure, activity, and specificity, thereby modulating virus release and virulence, and glycosylation at the catalytic domain affects its thermostability; however, glycosylation of M2 had no effect on its function. In addition, using IAV without the stalk and catalytic domains of NA as a live attenuated vaccine was shown to confer a strong IAVspecific CD8+ T-cell response and a strong cross-strain as well as cross-subtype protection against various virus strains.influenza A virus | glycosylation | vaccine design I nfluenza A viruses (IAV) belong to the Orthomyxoviridae family and can circulate widely and cross interspecies barriers through the highly antigenic drift and shift of the 18 subtypes of HA and 11 subtypes of neuraminidase (NA) (1, 2). In addition, the posttranslational modification of the IAV surface proteins is important to circumvent host defense and support the virus life cycle (3).HA is a major surface glycoprotein of IAV and is involved in viral infection via binding to sialic acid (SA)-containing glycans on the surface of host cell (3). The other major glycoprotein of IAV, NA, is involved in the cleavage of SA on the host cell receptor to facilitate the release of viral particles to infect other cells (4). M2, the third surface protein of IAV, has ion channel activity to regulate virus penetration and uncoating (1). All surface proteins interact with M1 protein for virus assembly and release (5).The modification of HA and NA by N-glycosylation is important in the IAV life cycle (1, 6-8). Previously, we have shown that the glycosylation of HA affects its receptor binding, immune response, and structural stability, and glycosite 27 is essential for retaining the structural integrity of HA and its receptor binding (6, 9). In addition, using the monoglycosylated HA as immunogen, it showed a broader protection against various IAV subtypes compared with the fully glycosylated version (10). However, it is not clear whether the other specific glycosites and their glycan structures on HA regulate its functions. With regard to NA, the functional roles of its glycosylation are not well understood, though N-glycosylation was reported to stabilize the protein from protease digestion and may affect the enzyme activity (11,12). The aim of this study was to understand the functional effects of glycosylation on HA, NA, and M2, and how glycosylation of the surface proteins affects the life cycle of IAV. ResultsGlycosylation of HA at N-142. Because several glycosylation sites (glycosites 27, 40, 176, 303, and 497) on HA are ...

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Section: Discussionmentioning

confidence: 62%

Influenza A surface glycosylation and vaccine design

Lin

Tsai

et al. 2016

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

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“…For normal virus budding, all virion components need to meet at the PM from where a membrane curvature protrudes, followed by the formation of a neck and finally membrane scission. All three viral integral membrane proteins have been implicated in this process (42)(43)(44). Despite the major effect nucleozin had on Rab11 localization (and thus presumably traffic throughout the recycling endosomal pathway), we did not detect any drug-induced alterations of the standard exocytic pathway or of the localization of HA, NA, and M2 (Fig.…”

Section: Discussionmentioning

confidence: 62%

Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection

Amorim

Kao

Digard

2013

J Virol

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dNovel antivirals are needed to supplement existing control strategies for influenza A virus (IAV). A promising new class of drug, exemplified by the compound nucleozin, has recently been identified that targets the viral nucleoprotein (NP). These inhibitors are thought to act as "molecular staples" that stabilize interactions between NP monomers, promoting the formation of nonfunctional aggregates. Here we detail the inhibitory mechanism of nucleozin, finding that the drug has both early-and late-acting effects on the IAV life cycle. When present at the start of infection, it inhibited viral RNA and protein synthesis. However, when added at later time points, it still potently blocked the production of infectious progeny but without affecting viral macromolecular synthesis. Instead, nucleozin blocked the cytoplasmic trafficking of ribonucleoproteins (RNPs) that had undergone nuclear export, promoting the formation of large perinuclear aggregates of RNPs along with cellular Rab11. This effect led to the production of much reduced amounts of often markedly smaller virus particles. We conclude that the primary target of nucleozin is the viral RNP, not NP, and this work also provides proof of the principle that IAV replication can be effectively inhibited by blocking cytoplasmic trafficking of the viral genome.

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“…Confluent MDCK cells either were infected (multiplicity of infection [MOI], 2) with recombinant influenza viruses or were mock infected with PBS for 1 h at 37°C. At 12 hpi, cells were lysed in 1ϫ SDS loading buffer as described previously (8,29). The reduced cell lysates were analyzed by Western blot analysis using MAbs against influenza A virus NP (HT103) (14), the PR8 HA head domain (PY102), the Cal/09 HA head domain (29E3) (11), and the VN/04 HA head domain (MAb 8) (19), as well as 12D1, a pan-H3 antibody reactive against the HA stalk (25).…”

Section: Cells and Virusesmentioning

confidence: 99%

Influenza Viruses Expressing Chimeric Hemagglutinins: Globular Head and Stalk Domains Derived from Different Subtypes

Hai

Krammer

Tan

et al. 2012

J Virol

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252

286

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The influenza virus hemagglutinin molecule possesses a globular head domain that mediates receptor binding and a stalk domain at the membrane-proximal region. We generated functional influenza viruses expressing chimeric hemagglutinins encompassing a variety of globular head and stalk combinations, not only from different hemagglutinin subtypes but also from different hemagglutinin phylogenetic groups. These chimeric recombinant viruses possess growth properties similar to those of wildtype influenza viruses and can be used as reagents to measure domain-specific antibodies in virological and immunological assays.

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Budding Capability of the Influenza Virus Neuraminidase Can Be Modulated by Tetherin

Cited by 86 publications

References 67 publications

Influenza A surface glycosylation and vaccine design

Influenza A surface glycosylation and vaccine design

Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection

Influenza Viruses Expressing Chimeric Hemagglutinins: Globular Head and Stalk Domains Derived from Different Subtypes

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