Virokinin, a bioactive peptide of the tachykinin family, is released from the fusion protein of bovine respiratory syncytial virus.
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 post-translational 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 beta-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.
Zimmer
Gert
G
Institut für Virologie, Tierärztliche Hochschule Hannover, Bünteweg 17, D-30559 Hannover, Germany.
Rohn
Michael
M
McGregor
Gerard P
GP
Schemann
Michael
M
Conzelmann
Karl-Klaus
KK
Herrler
Georg
G
D000818:Animals; D002417:Cattle; D045683:Furin / Q000378:metabolism; D018716:Molecular Mimicry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D018039:Receptors, Tachykinin / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000209:etiology / Q000662:veterinary; D018112:Respiratory Syncytial Virus, Bovine / Q000737:chemistry*; D013552:Swine; D015320:Tachykinins / Q000378:metabolism* / Q000494:pharmacology; D014760:Viral Fusion Proteins / Q000378:metabolism*
D018039:Receptors, Tachykinin; D015320:Tachykinins; D014760:Viral Fusion Proteins; D045683:Furin