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J. Biol. Chem., Vol. 278, Issue 47, 46854-46861, November 21, 2003

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

Gert Zimmer, Michael Rohn, Gerard P. McGregor¶, Michael Schemann, Karl-Klaus Conzelmann||, and Georg Herrler**

From the Institut für Virologie, Tierärztliche Hochschule Hannover, Bünteweg 17, D-30559 Hannover, Germany, Lehrstuhl für Humanbiologie, TU München, Hochfeldweg 2, D-85350 Freising-Weihenstephan, Germany, ^¶Institut für Normale und Pathologische Physiologie, Philipps-Universität Marburg, Deutschhausstrasse 1-2, D-35037 Marburg, Germany, and ^||Max-von-Pettenkofer-Institut und Genzentrum, Ludwig-Maximillians-Universität, Feodor-Lynen-Strasse 25, D-81377 München, Germany

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 -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.

Received for publication, June 30, 2003 , and in revised form, August 19, 2003.

^* This work was supported by European Community Grant QLK2-CT-1999-00443 and Deutsche Forschungsgemeinschaft Grants HE 1168/11-1/2 and SFB 587 (to G. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Institut für Virologie, Tierärztliche Hochschule Hannover, Bünteweg 17, D-30559 Hannover, Germany. Fax: 49-511-953-8898; E-mail: Georg.Herrler{at}tiho-hannover.de.

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