JBC：德发现一种细菌毒素可致细胞自杀

德国研究人员最新研究发现，一种细菌毒素可致细胞内的一种蛋白失活，致使细胞“自杀”。这一发现或有助于研究杀死癌细胞。相关论文发表在近期的《生物化学杂志》（<em>Journal of Biochemistry</em>）上。

德国弗赖堡大学8月1日发表新闻公报说，该校研究人员发现，可导致气性坏疽的产气荚膜梭菌可产生一种名为“Tpel”的梭菌毒素，这种毒素可将糖分子附着在宿主细胞的Ras蛋白上，以干扰这种蛋白的自然功能。

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弗赖堡大学药理学家克劳斯·阿克托里斯介绍，人类细胞中的Ras蛋白在激发细胞生长时发挥重要作用，而Tpel毒素则会改变这种蛋白，让其无法促进细胞生长，最终导致细胞死亡。

阿克托里斯说，人类癌细胞中常出现Ras蛋白的变种，这种蛋白在癌症形成中起到重要作用，如果能够以变种Ras蛋白为靶细胞，利用这种毒素发挥作用，也许能致使癌细胞“自杀”。研究人员目前正在进行进一步研究。 
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<a title="" href="http://dx.doi.org/10.1074/jbc.M112.347773" target="_blank">doi:10.1074/jbc.M112.347773</a>
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<br/><strong>Molecular characteristics of Clostridium perfringens TpeL toxin and consequences of mono-O-GlcNAcylation of Ras in living cells </strong><br/>


Gregor Guttenberg, Sven Hornei, Thomas Jank, Carsten Schwan, Wei Lü, Oliver Einsle, Panagiotis Papatheodorou and Klaus Aktories*

TpeL is a member of the family of clostridial glucosylating toxins produced by Clostridium perfringens type A, B and C strains. In contrast to other members of this toxin family, it lacks a C-terminal polypeptide repeat domain, which is suggested to be involved in target cell binding. It was shown that the glucosyltransferase domain of TpeL modifies Ras in vitro by mono-O-glucosylation or mono-O-GlcNAcylation (Nagahama, M., Ohkubo, A., Oda, M., Kobayashi, K., Amimoto, K., Miyamoto, K., and Sakurai, J. (2011) Infect. Immun. 79, 905-910). Here we show that TpeL preferably utilizes UDP-N-acetylglucosamine (UDP-GlcNAc) as a sugar donor. Change of alanine-383 of TpeL to isoleucine turns the sugar donor preference from UDP-GlcNAc to UDP-glucose. In contrast to previous studies, we show that Rac is a poor substrate in vitro and in vivo and requires 1-2 magnitudes higher toxin concentrations for modification by TpeL. The toxin is autoproteolytically processed in the presence of inositol hexakisphosphate (InsP6) by an intrinsic cysteine protease domain, located next to the glucosyltransferase domain. A C-terminally extended TpeL full-length variant (TpeL1-1779) induces apoptosis in HeLa cells (most likely by mono-O-GlcNAcylation of Ras), and inhibits Ras signaling including Ras-Raf interaction and ERK activation. In addition, TpeL blocks Ras signaling in rat pheochromocytoma PC12 cells. TpeL is a glucosylating toxin, which modifies Ras and induces apoptosis in target cells without having

<br/>来源：新华网

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