Characterization of the Carboxypeptidase Involved in the Proteolytic Cleavage of the Influenza Haemagglutinin

Garten, Wolfgang; Klenk, Hans‐Dieter

doi:10.1099/0022-1317-64-10-2127

Cited by 40 publications

(19 citation statements)

References 38 publications

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“…In addition, the sequences downstream of this motif contain all of the information necessary for the maturation of a tachykinin peptide. The basic motif KKRKRR 136 provides a target for endoproteolytic cleavage by prohormone convertases (34) and subsequent trimming by carboxypeptidases (35). The glycine residue, Gly 130 , carboxyl-terminal to the tachykinin motif provides the NH 2 group for C-terminal amidation by peptidylglycine ␣-amidating mono-oxygenase (36).…”

Section: Resultsmentioning

confidence: 99%

Virokinin, a Bioactive Peptide of the Tachykinin Family, Is Released from the Fusion Protein of Bovine Respiratory Syncytial Virus

Zimmer

Rohn

McGregor

et al. 2003

Journal of Biological Chemistry

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Tachykinins, an evolutionary conserved family of peptide hormones in both invertebrates and vertebrates, are produced by neuronal cells as inactive preprotachykinins that are post-translationally processed into different neuropeptides such as substance P, neurokinin A, and neurokinin B. We show here that furin-mediated cleavage of the bovine respiratory syncytial virus fusion protein results in the release of a peptide that is converted into a biologically active tachykinin (virokinin) by additional posttranslational modifications. An antibody directed to substance P cross-reacted with the C terminus of mature virokinin that contains a classical tachykinin motif. The cellular enzymes involved in the C-terminal maturation of virokinin were found to be present in many established cell lines. Virokinin is secreted by virus-infected cells and was found to act on the tachykinin receptor 1 (TACR1), leading to rapid desensitization of this G protein-coupled receptor as shown by TACR1-green fluorescent protein conjugate translocation from the cell surface to endosomes and by co-internalization of the receptor with ␤-arrestin 1-green fluorescent protein conjugates. In vitro experiments with isolated circular muscle from guinea pig stomach indicated that virokinin is capable of inducing smooth muscle contraction by acting on the tachykinin receptor 3. Tachykinins and their cognate receptors are present in the mammalian respiratory tract, where they have potent effects on local inflammatory and immune processes. The viral tachykinin-like peptide represents a novel form of molecular mimicry, which may benefit the virus by affecting the host immune response. Bovine respiratory syncytial virus (BRSV)1 and human respiratory syncytial virus (HRSV), two closely related RNA viruses of the family Paramyxoviridae, replicate in the lower respiratory tract, causing similar diseases in their respective hosts (1). Young calves and infants are particularly affected and suffer from obstructive bronchitis, wheezing, and hypoxemia. Damage of respiratory epithelial cells due to the infection itself probably plays a minor role in RSV pathogenesis (2). Rather, the inflammatory response triggered by cellular chemokines and cytokines that are released from RSV-infected epithelial cells and lymphocytes is believed to contribute to the severity of the disease (3-9).Several observations indicate that the adaptive immune response to RSV is incomplete and of short duration. Maternally derived virus-neutralizing antibodies do not provide sufficient protection from infection (10, 11). Reinfections, even by RSV of the same serogroup, occur repeatedly during childhood and throughout life (12, 13). There is also evidence that infection with HRSV contributes to increased airway hyperresponsiveness and asthma (14 -17). Recent data suggest that RSV has immunosuppressive properties. In the mouse model, HRSV infection causes suppression of lung CD8 ϩ T-cell effector activity and inhibition of pulmonary CD8 ϩ T-cell memory development (18). In BRSV-infected la...

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Section: Resultsmentioning

confidence: 99%

Virokinin, a Bioactive Peptide of the Tachykinin Family, Is Released from the Fusion Protein of Bovine Respiratory Syncytial Virus

Zimmer

Rohn

McGregor

et al. 2003

Journal of Biological Chemistry

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“…Sturman & Holmes (1977) have shown that the MHV-A59 S polypeptide can be cleaved by trypsin and it appears likely that coronaviruses, in common with many enveloped RNA viruses, utilize a cellular trypsin-like endoprotease activity to achieve proteolytic processing. It is not yet known whether a second, carboxypeptidase, enzyme plays a role in the maturation of the coronavirus S protein, as has been shown for the influenza virus haemagglutinin (Garten & Klenk, 1983).…”

Section: Discussionmentioning

confidence: 99%

Nucleotide Sequence of the Gene Encoding the Surface Projection Glycoprotein of Coronavirus MHV-JHM

Schmidt

Skinner

Siddell

1987

Journal of General Virology

115

114

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SUMMARYSequences encoding the surface projection glycoprotein of the coronavirus, murine hepatitis virus (MHV), strain JHM, have been cloned into pAT153 using cDNA produced by priming with specific oligonucleotides on infected cell RNA. The regions of three clones pJMS1010, pJS112 and pJS92, which together encompass the surface protein gene have been sequenced by the chain termination method. The sequence of the primary translation product, deduced from the DNA sequence, predicts a polypeptide of 1235 amino acids with a molecular weight of 136600. This polypeptide displays the features characteristic of a group 1 membrane protein; an amino-terminal signal sequence and carboxy-terminal membrane and cytoplasmic domains. There are 21 potential glycosylation sites in the polypeptide and a cysteine-rich region in the vicinity of the transmembrane domain. During maturation proteolytic processing of the polypeptide occurs and at positions 624 to 628 the sequence Arg Arg-Ala-ArgArg is found, which is similar to a number of basic sequences involved in the cleavage of enveloped RNA virus glycoproteins. The fusogenic properties of the MHV surface protein do not appear to correlate with a strongly hydrophobic region at the putative amino terminus of the carboxy-terminat cleavage product.

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“…Only one nucleotide substitution could change the -R-S-S-Rmotif to -R-S-R-R-. it was (13)(14)(15)(16)(17)(18) suggested that H9N2 viruses isolates in Iran are potentially capable of becoming highly pathogenic. The presence of Serine amino acid has made it a crucial motif because only 1 nucleotide substitution (C to A or G) at two positions is enough to convert this motif to a virulent sequence.…”

Section: Discussionmentioning

confidence: 99%

“…In the course of the infection, HAO is cleaved into two disulfidelinked polypeptide chains, HAl and HA2 (13). The cleavage site of 13 from 15 HA subtypes (all HA subtypes except H5 and H7) consist of four amino acids including a single arginine residue which is removed from the COOH terminus of the HAl after cleavage by means of virus-associated carboxypeptidase (14). A correlation between cleavability of the HAO and pathogenicity has been established.…”

Section: Introductionmentioning

confidence: 99%

Amino Acid Sequence Analysis of Hemagglutinin Protein of H9N2 Isolated from Broilers in Tehran in 2007

et al. 2010

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Background and Aims: Since 1998, Iranian poultry industry has been affected by avian influenza (AI) virus, subtype H9N2. The association of high mortality and case report of H5N1 and H9N2 influenza virus in wild birds in recent years raised the suspicion of a possible new genetic modified AI virus. Methods: Partial nucleotide sequences and deduced amino acid of hemagglutinin (HA) genes of 4 H9N2 influenza viruses isolated from broilers in Iran in 2007 were genetically analyzed. Results: The isolates possessed two types of amino acid motif -R-S-S-RlG-L-and -R-S-N-RlG-L-at the cleavage site of HA. "-R-S-N-RlG-L in Iranian isolates is the same as the motif previously reported in Israel. Glycosylation site of the virus has been missed in some isolates. Receptor binding site of the isolates were found similar to the human H9N2 isolates. Conclusion: Based on published reports for high similarity of H9N2 with human H5N1 isolates, it is important to consider the potential of Iranian avian influenza viruses to infect human.

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Characterization of the Carboxypeptidase Involved in the Proteolytic Cleavage of the Influenza Haemagglutinin

Cited by 40 publications

References 38 publications

Virokinin, a Bioactive Peptide of the Tachykinin Family, Is Released from the Fusion Protein of Bovine Respiratory Syncytial Virus

Virokinin, a Bioactive Peptide of the Tachykinin Family, Is Released from the Fusion Protein of Bovine Respiratory Syncytial Virus

Nucleotide Sequence of the Gene Encoding the Surface Projection Glycoprotein of Coronavirus MHV-JHM

Amino Acid Sequence Analysis of Hemagglutinin Protein of H9N2 Isolated from Broilers in Tehran in 2007

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