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，新合成的蛋白质传递到内体和溶酶体以及细胞表面取决于独特的细胞器，即“高尔基体设备”，该器将蛋白质分为最终目的地。输送到内体和溶酶体的蛋白质包括大量多样的水解酶和非酶激活蛋白。它们是通过两个甘露糖 - 6-磷酸受体（MPRS）引导的。最近，我们发现使用替代分选受体“ sortilin”的溶酶体激活蛋白“ prosaposin”运输到内体和溶酶体。我们还发现，占用末端段的删除消除了其运输到内体和溶酶体。突变分析使我们能够确定所谓的Prosaposin“ C-terminus”中的一个小片段包含其与Tortilin结合及其传输到内体和溶酶体所需的独特基序。确定的序列可以允许开发新的治疗方法，以靶向具有抗疾病特性的蛋白质对内体和溶酶体。鉴于大多数已知的病原体通过内体和溶酶体的内吞途径穿透细胞，我们的方法可能对破坏这些隔室内的病原体很有用。因此，本研究可能会建立概念证明，并为没有可用治疗的动物和人类提供替代性治疗。