Zimmer Gert, Rohn Michael, McGregor Gerard P, Schemann Michael, Conzelmann Karl-Klaus, Herrler Georg
Institut für Virologie, Tierärztliche Hochschule Hannover, Bünteweg 17, D-30559 Hannover, Germany.
J Biol Chem. 2003 Nov 21;278(47):46854-61. doi: 10.1074/jbc.M306949200. Epub 2003 Sep 2.
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.
速激肽是在无脊椎动物和脊椎动物中进化保守的肽类激素家族，由神经元细胞产生，最初是以无活性的前速激肽原形式存在，经翻译后加工成为不同的神经肽，如P物质、神经激肽A和神经激肽B。我们在此表明，弗林蛋白酶介导的牛呼吸道合胞病毒融合蛋白的切割导致一种肽的释放，该肽通过额外的翻译后修饰转化为具有生物活性的速激肽（病毒激肽）。一种针对P物质的抗体与成熟病毒激肽的C末端发生交叉反应，该C末端包含一个经典的速激肽基序。发现参与病毒激肽C末端成熟的细胞酶存在于许多已建立的细胞系中。病毒激肽由病毒感染的细胞分泌，并被发现作用于速激肽受体1（TACR1），导致该G蛋白偶联受体迅速脱敏，这表现为TACR1-绿色荧光蛋白共轭物从细胞表面转移至内体，以及该受体与β-抑制蛋白1-绿色荧光蛋白共轭物共同内化。用豚鼠胃分离的环形肌进行的体外实验表明，病毒激肽能够通过作用于速激肽受体3诱导平滑肌收缩。速激肽及其同源受体存在于哺乳动物呼吸道中，它们在局部炎症和免疫过程中具有强大作用。病毒类速激肽样肽代表了一种新型的分子模拟形式，可能通过影响宿主免疫反应而使病毒受益。
