The cytoplasmic tail of the influenza C virus glycoprotein HEF negatively affects transport to the cell surface.

Oeffner, Frank; Klenk, Hans‐Dieter; Herrler, Georg

doi:10.1099/0022-1317-80-2-363

Cited by 7 publications

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References 19 publications

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“…Our data contrast with previously published reports on the expression of HEF-JHB from cDNA (14,20,25). When expressed from cDNA, the HEF-JHB glycoprotein accumulates in an 80-kDa, presumably misfolded, form and is retained in the endoplasmic reticulum (25).…”

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confidence: 99%

“…Under nonreducing conditions, the HEF-AA glycoprotein also migrated as a single 90-kDa band, although some heterogeneity was detected after incubation in chase medium for 0, 10, and 20 min, most likely resulting from a lack of proper disulfide bond formation. Conversion of HEF-AA from an 80-to a 100-kDa form under nonreducing conditions, an event associated with but not sufficient to confer cell surface transport of HEF-JHB (14,25), was not observed.…”

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confidence: 85%

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confidence: 99%

“…Analysis at the cell surface of the three biological activities of HEF has been hindered by an apparent lack of surface transport of the glycoprotein in mammalian cells when the cDNA was derived from influenza C virus strain C/Johannes-burg/1/66 (HEF-JHB) (14,20,25), although erythrocyte binding has been observed when the C/California/78 HEF cDNA was expressed in cells (26). The lack of surface transport of HEF-JHB has been attributed to a negative regulatory domain (Arg-Thr-Lys) which compromises the predicted cytoplasmic tail of HEF (14). We have studied the expression from cDNA of the HEF glycoproteins from influenza C/Ann Arbor/1/50 virus (HEF-AA) and influenza C/Taylor/1233/47 virus (HEF-Tay) and have determined that the HEF glycoprotein of both strains is transported to the cell surface and exhibits the three known biological activities of HEF when expressed in a variety of cell types and in a variety of expression systems.…”

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Cell Surface Expression of Biologically Active Influenza C Virus HEF Glycoprotein Expressed from cDNA

Pekosz

Lamb

1999

J Virol

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The hemagglutinin, esterase, and fusion (HEF) glycoprotein of influenza C virus possesses receptor binding, receptor destroying, and membrane fusion activities. The HEF cDNAs from influenza C/Ann Arbor/1/50 (HEF-AA) and influenza C/Taylor/1223/47 (HEF-Tay) viruses were cloned and expressed, and transport of HEF to the cell surface was monitored by susceptibility to cleavage by exogenous trypsin, indirect immunofluorescence microscopy, and flow cytometry. Previously it has been found in studies with the C/Johannesburg/1/66 strain of influenza C virus (HEF-JHB) that transport of HEF to the cell surface is severely inhibited, and it is thought that the short cytoplasmic tail, Arg-Thr-Lys, is involved in blocking HEF cell surface expression (F. Oeffner, H.-D. Klenk, and G. Herrler, J. Gen. Virol. 80:363–369, 1999). As the cytoplasmic tail amino acid sequences of HEF-AA and HEF-Tay are identical to that of HEF-JHB, the data indicate that cell surface expression of HEF-AA and HEF-Tay is not inhibited by this amino acid sequence. Furthermore, the abundant cell surface transport of HEF-AA and HEF-Tay indicates that their cell surface expression does not require coexpression of another viral protein. The HEF-AA and HEF-Tay HEF glycoproteins bound human erythrocytes, promoted membrane fusion in a low-pH and trypsin-dependent manner, and displayed esterase activity, indicating that the HEF glycoprotein alone mediates all three known functions at the cell surface.

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Cell Surface Expression of Biologically Active Influenza C Virus HEF Glycoprotein Expressed from cDNA

Pekosz

Lamb

1999

J Virol

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“…Haemagglutinin esterase encoded by the fourth segment forms thorns on the surface of virus and have three biological functions: binds cell receptors, destroys receptors (acetylesterase activity), and pos sesses the ability for fusion to cell membrane (penetra tion activity) [17][18][19][20][21]. The three dimensional struc ture of HEF consisting of three domains responsible for the indicated biological functions of the protein has been establised [19].…”

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Genetic diversity and evolution of the influenza C virus

et al. 2012

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The influenza C virus is spread worldwide and causes diseases of the upper and (less frequently) lower respiratory tract in human. The virus is not pandemic, but it circulates together with pandemic influ enza A and B viruses during winter months and has quite similar clinical manifestations. The influenza C virus is also encountered in animals (pigs and dogs) and is known to override the interspecific barriers of transmssion. The immune system of mammals often fails to recognize new antigenic variants of influenza C virus, which invariably arise in nature, resulting in outbreaks of diseases, although the structure of antigens in influenza C virus in general is much more stable than those of influenza viruses A and B. Variability of genetic information in natural isolates of viruses is determined by mutations, reassortment, and recombination. However, recombination events very rarely occur in genomes of negative strand RNA viruses, including those of influenza, and virtually have no effect on their evolution. Unambiguous explanations for this phenomenon have thus far not been proposed. There is no proof of recombination processes in the influenza C virus genome. On the contrary, reassortant viruses derived from different strains of influenza C virus frequently appear in vitro and are likely to be common in nature. The genome of influenza C virus comprises seven seg ments. Based on the comparison of sequences in one of its genes (HEF), six genetic or antigenic lineages of this virus can be distinguished (Yamagata/26/

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Role of Individual Oligosaccharide Chains in Antigenic Properties, Intracellular Transport, and Biological Activities of Influenza C Virus Hemagglutinin-Esterase Protein

et al. 2001

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The hemagglutinin-esterase (HE) glycoprotein of influenza C virus is composed of three domains: a stem domain active in membrane fusion (F), an acetylesterase domain (E), and a receptor-binding domain (R). The protein contains eight N-linked glycosylation sites, four (positions 26, 395, 552, and 603) in the F domain, three (positions 61, 131, and 144) in the E domain, and one (position 189) in the R domain. Here, we investigated the role of the individual oligosaccharide chains in antigenic properties, intracellular transport, and biological activities of the HE protein by eliminating each of the glycosylation sites by site-specific mutagenesis. Comparison of electrophoretic mobility between the wild-type and the mutant proteins showed that while seven of the glycosylation sites are used, one (position 131) is not. Analysis of reactivity of the mutants with anti-HE monoclonal antibodies demonstrated that glycosylation at position 144 is essential for the formation of conformation-dependent epitopes. It was also evident that glycosylation at the two sites in the F domain (positions 26 and 603), in addition to that in the E domain (position 144), is required for the HE molecule to be transported from the endoplasmic reticulum and that mutant HEs lacking one of these three sites failed to undergo the trimer assembly. Removal of an oligosaccharide chain at position 144 or 189 resulted in a decrease in the esterase activity. By contrast, two mutants lacking an oligosaccharide chain at position 26 or 603, which were defective not only in cell surface expression but in trimerization, possessed full-enzyme activity, suggesting that the HE monomers present within the cell have acetylesterase activity. Fusion activity of cells expressing each of mutant HEs was found to be comparable with the ability of the protein to be transported to the cell surface, suggesting that there is no specific oligosaccharide chain that plays a critical role in promoting membrane fusion.

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The cytoplasmic tail of the influenza C virus glycoprotein HEF negatively affects transport to the cell surface.

Cited by 7 publications

References 19 publications

Cell Surface Expression of Biologically Active Influenza C Virus HEF Glycoprotein Expressed from cDNA

Cell Surface Expression of Biologically Active Influenza C Virus HEF Glycoprotein Expressed from cDNA

Genetic diversity and evolution of the influenza C virus

Role of Individual Oligosaccharide Chains in Antigenic Properties, Intracellular Transport, and Biological Activities of Influenza C Virus Hemagglutinin-Esterase Protein

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