A Serpin Shapes the Extracellular Environment to Prevent Influenza A Virus Maturation

Dittmann, Meike; Hoffmann, Hans-Heinrich; Scull, Margaret A.; Gilmore, Rachel H.; Bell, Kierstin L.; Ciancanelli, Michael J.; Wilson, Sam J.; Crotta, Stefania; Yu, Yingpu; Flatley, Brenna R.; Xiao, Jing; Casanova, Jean‐Laurent; Wack, Andreas; Bieniasz, Paul D.; Rice, Charles M.

doi:10.1016/j.cell.2015.01.040

Cited by 141 publications

(184 citation statements)

References 53 publications

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“…In addition, a very recent observation that plasminogen activator inhibitor 1 (PAI-1) inhibits HA cleavage and thereby reduces infectivity of progeny viruses also supports the concept of antiviral treatment by application of specific protease inhibitors (Dittmann et al, 2015). The increasing results from literature together with our data suggest that optimized synthetic protease inhibitors, especially in combination with other antiviral agents, can be useful drugs for a new and more efficient influenza treatment.…”

Section: Inhibition Of Ha-activating Host Proteases Prevents Virus Prsupporting

confidence: 75%

Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Garten

Braden

Arendt

et al. 2015

European Journal of Cell Biology

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Section: Inhibition Of Ha-activating Host Proteases Prevents Virus Prsupporting

confidence: 75%

Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Garten

Braden

Arendt

et al. 2015

European Journal of Cell Biology

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“…The analysis of the coclustering of M2 and HA gave a curve indicating strong interactions over the entire distance measured. M2 is not concentrated in lipid rafts, unlike HA; thus, the distribution observed may reflect M2 interacting with a membrane domain rather than HA itself (30,32,39,63,64). While the distribution of mut1M2 compared to HA was not random in nature, it was reduced by ϳ70% from that seen for wild-type (wt) M2 at 100 nm ( Fig.…”

Section: Resultsmentioning

confidence: 88%

“…However, evidence for these interactions, although indicated by genetic experiments, have been difficult to demonstrate at the biochemical level. A role for host cell proteins in budding has been proposed, e.g., RAB11A, (74), tetraspanin CD81 (75), the UBR4 ubiquitin ligase (which associates with the M2 cytoplasmic tail and promotes apical transport) (76), and a serpin necessary to cleave HA (64).…”

Section: Discussionmentioning

confidence: 99%

Lateral Organization of Influenza Virus Proteins in the Budozone Region of the Plasma Membrane

Leser

Lamb

2017

J Virol

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Influenza virus assembles and buds at the plasma membrane of virusinfected cells. The viral proteins assemble at the same site on the plasma membrane for budding to occur. This involves a complex web of interactions among viral proteins. Some proteins, like hemagglutinin (HA), NA, and M2, are integral membrane proteins. M1 is peripherally membrane associated, whereas NP associates with viral RNA to form an RNP complex that associates with the cytoplasmic face of the plasma membrane. Furthermore, HA and NP have been shown to be concentrated in cholesterol-rich membrane raft domains, whereas M2, although containing a cholesterol binding motif, is not raft associated. Here we identify viral proteins in planar sheets of plasma membrane using immunogold staining. The distribution of these proteins was examined individually and pairwise by using the Ripley K function, a type of nearest-neighbor analysis. Individually, HA, NA, M1, M2, and NP were shown to self-associate in or on the plasma membrane. HA and M2 are strongly coclustered in the plasma membrane; however, in the case of NA and M2, clustering depends upon the expression system used. Despite both proteins being raft resident, HA and NA occupy distinct but adjacent membrane domains. M2 and M1 strongly cocluster, but the association of M1 with HA or NA is dependent upon the means of expression. The presence of HA and NP at the site of budding depends upon the coexpression of other viral proteins. Similarly, M2 and NP occupy separate compartments, but an association can be bridged by the coexpression of M1.IMPORTANCE The complement of influenza virus proteins necessary for the budding of progeny virions needs to accumulate at budozones. This is complicated by HA and NA residing in lipid raft-like domains, whereas M2, although an integral membrane protein, is not raft associated. Other necessary protein components such as M1 and NP are peripherally associated with the membrane. Our data define spatial relationships between viral proteins in the plasma membrane. Some proteins, such as HA and M2, inherently cocluster within the membrane, although M2 is found mostly at the periphery of regions of HA, consistent with the proposed role of M2 in scission at the end of budding. The association between some pairs of influenza virus proteins, such as M2 and NP, appears to be brokered by additional influenza virus proteins, in this case M1. HA and NA, while raft associated, reside in distinct domains, reflecting their distributions in the viral membrane.

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“…MetaboAnalyst is a free, webbased tool that combines results from powerful pathway analysis and pathway topology analysis to help researchers c identify the most relevant pathways involved in the conditions under study. This tool uses high-quality KEGG metabolic pathways as the backend knowledgebase and integrates many well-established methods and novel algorithms into its pathway analysis [43]. MetaboAnalyst can also provide an interactive visualization system to deliver the analysis results in an intuitive manner.…”

Section: Resultsmentioning

confidence: 99%

The study on serum and urine of renal interstitial fibrosis rats induced by unilateral ureteral obstruction based on metabonomics and network analysis methods

et al. 2016

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Transmission of biological information is a biochemical process of multistep cascade from genes/proteins to metabolites. However, because most metabolites reflect the terminal information of the biochemical process, it is difficult to describe the transmission process of disease information in terms of the metabolomics strategy. In this paper, by incorporating network and metabolomics methods, an integrated approach was proposed to systematically investigate and explain the molecular mechanism of renal interstitial fibrosis. Through analysis of the network, the cascade transmission process of disease information starting from genes/proteins to metabolites was putatively identified and uncovered. The results indicated that renal fibrosis was involved in metabolic pathways of glycerophospholipid metabolism, biosynthesis of unsaturated fatty acids and arachidonic acid metabolism, riboflavin metabolism, tyrosine metabolism, and sphingolipid metabolism. These pathways involve kidney disease genes such as TGF-β1 and P2RX7. Our results showed that combining metabolomics and network analysis can provide new strategies and ideas for the interpretation of pathogenesis of disease with full consideration of "gene-protein-metabolite."

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A Serpin Shapes the Extracellular Environment to Prevent Influenza A Virus Maturation

Cited by 141 publications

References 53 publications

Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Lateral Organization of Influenza Virus Proteins in the Budozone Region of the Plasma Membrane

The study on serum and urine of renal interstitial fibrosis rats induced by unilateral ureteral obstruction based on metabonomics and network analysis methods

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