Novel strategy to intercept pathogens at the site of cellular entry

在细胞进入位点拦截病原体的新策略

• 批准号: 183639-2011
• 负责人: Morales, Carlos
• 金额: $ 2.91万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=476385
• 关键词: Novel; strategy; intercept; pathogens; site

In eukaryotic cells the delivery of newly synthesized proteins to the endosomes and lysosomes and to the cell surface is dependent on a unique organelle, the "Golgi apparatus", which sorts and targets proteins to their final destination. Proteins delivered to the endosomes and lysosomes include a large and diverse class of hydrolytic enzymes and nonenzymic activator proteins. They are directed away via two mannose-6-phosphate receptors (MPRs). Recently, we found that the lysosomal activator protein "prosaposin" traffics to the endosomes and lysosomes using the alternative sorting receptor, "sortilin". We also found that deletion of the terminal segment of prosaposin abolished its transport to the endosomes and lysosomes. Mutational analysis allowed us to identify that a small segment within the so-called prosaposin "C-terminus" contains a unique motif required for its binding to sortilin and its transport to the endosomes and lysosomes. The identified sequence may permit the development of new therapeutic approaches for the targeting of proteins with anti-pathogenic properties to the endosomes and lysosomes. Given that most of the known pathogens penetrate the cell via the endocytic pathway at the endosomes and lysosomes, our approach may be useful to destroy the pathogens within these compartments. Thus, the present research may establish a proof of concept and offer alternative treatments for infectious diseases in animals and humans for which there are no treatment available.

在真核细胞中，将新合成的蛋白质递送到内体和溶酶体以及细胞表面依赖于独特的细胞器，即“高尔基体”，其将蛋白质分类并靶向其最终目的地。递送到内体和溶酶体的蛋白质包括大量且不同种类的水解酶和非酶激活蛋白。它们通过两个甘露糖-6-磷酸受体（MPR）被引导离开。最近，我们发现溶酶体激活蛋白“saposin”通过选择性分选受体“sortilin”转运到内体和溶酶体。我们还发现，saposin原的末端片段的删除取消其运输到内体和溶酶体。突变分析使我们能够鉴定出所谓的鞘脂激活蛋白原“C-末端”内的一个小片段含有其与分拣蛋白结合并转运至内体和溶酶体所需的独特基序。所鉴定的序列可以允许开发新的治疗方法，用于将具有抗病原特性的蛋白质靶向到内体和溶酶体。鉴于大多数已知的病原体通过内吞途径在内体和溶酶体处渗透细胞，我们的方法可能有助于破坏这些隔室中的病原体。因此，目前的研究可以建立一个概念验证，并为动物和人类的传染病提供替代治疗，因为没有可用的治疗方法。