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首页> 外文期刊>Cell motility and the cytoskeleton >Helicobacter pylori activates protein kinase C delta to control Raf in MAP kinase signalling: role in AGS epithelial cell scattering and elongation.
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Helicobacter pylori activates protein kinase C delta to control Raf in MAP kinase signalling: role in AGS epithelial cell scattering and elongation.

机译：幽门螺杆菌激活蛋白激酶C Delta以控制RAF在MAP激酶信号传导中：AGS上皮细胞散射和伸长的作用。

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摘要

Helicobacter pylori is a major etiological agent in the development of chronic gastritis, duodenal ulcer and gastric carcinoma in humans. Virulent H. pylori strains harbor a type IV secretion system (T4SS) encoded by the cag pathogenicity island. This T4SS injects the CagA protein into gastric epithelial cells leading to actin-cytoskeletal rearrangements followed by cell elongation and scattering. Here we report that PMA (4beta-phorbol-12-myristate-13-acetate), a well-known cell-permeable activator of protein kinase C (PKC), induces a remarkably similar cellular phenotype as compared to infection with H. pylori. PKCs comprise a large family of serine/threonine kinases which are important for multiple physiological processes of host cells. We therefore investigated the role of individual PKC members and the signalling pathways involved in phenotypical outcome. Using isoform-specific silencing RNAs and pharmacological inhibitors we found that two isoforms, PKC-alpha and PKC-delta, were essential for both PMA- and H. pylori-induced elongation phenotype. Furthermore, we provide evidence that PKC-delta activity is profoundly stimulated during the course of infection using activation-specific antibodies against PKC phosphorylated at threonine residue 505 or serine residue 660. Infection with H. pylori wild-type and mutants showed that at least two bacterial factors activate PKC-delta in a time-dependent manner, one of which is CagA. Immunofluorescence microscopy studies further demonstrated that phosphorylated PKC-delta is accumulated and recruited to dynamic actin-structures at the cell membrane. Finally, we show that PKC-delta specifically targets Raf kinase to stimulate the Erk1/2 kinase pathway, which is also crucial for phenotypical outcome. Thus, PKC-delta is another important mediator of H. pylori-induced pathogenesis.
机译：幽门螺杆菌是一种在人类慢性胃炎，十二指肠溃疡和胃癌的发展中的主要原因。毒性H.幽门螺杆菌菌株涉及CAG致病性岛编码的IV型分泌系统（T4S）。该T4SS将CAGA蛋白注射到胃上皮细胞中，导致肌动蛋白 - 细胞骨骼重排，然后是细胞伸长和散射。在这里，我们报告称PMA（4beta-phorbol-12-myristerate-13-醋酸酯），众所周知的蛋白质激酶C（PKC）的细胞可渗透的活化剂，与H. pylori感染相比，诱导相似的细胞表型。 PKCS包含大族丝氨酸/苏氨酸激酶，这对于宿主细胞的多种生理过程很重要。因此，我们调查了个体PKC成员和表型结果所涉及的信号通路的作用。使用特异性沉默RNA和药理学抑制剂，我们发现两种同种型，PKC-α和PKC-DELTA对PMA和H.幽门螺杆菌诱导的伸长表型是必不可少的。此外，我们提供了证据表明，在使用苏氨酸残基505或丝氨酸残基660的PKC磷酸化的活化特异性抗体在感染过程中，PKC-DELTA活性在感染过程中刺激。用H.幽门螺杆菌野生型和突变体感染至少两个细菌因子以时间依赖的方式激活PKC-DELTA，其中一个是CAGA。免疫荧光显微镜研究进一步证明了磷酸化的PKC-DELTA被积聚并募集到细胞膜的动态肌动蛋白结构。最后，我们表明PKC-DELTA专门针对RAF激酶刺激ERK1 / 2激酶途径，这对于表型结果也至关重要。因此，PKC-DELTA是H.幽门螺杆菌诱导的发病机制的另一个重要介体。

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