Novel strategy to intercept pathogens at the site of cellular entry

在真核细胞中，将新合成的蛋白质输送到内小体和溶酶体以及细胞表面依赖于一个独特的细胞器，即“高尔基体”，它对蛋白质进行分类并将其定位到最终目的地。递送到内体和溶酶体的蛋白质包括一大类不同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“丙皂苷”通过另一种分选受体“sortilin”转运到内小体和溶酶体。我们还发现，丙皂苷末端片段的缺失取消了它向内体和溶酶体的运输。突变分析使我们能够确定所谓的丙皂苷“C-末端”中的一小段包含一个独特的基序，这是其与山梨素结合以及向内体和溶酶体转运所必需的。所鉴定的序列可能允许开发新的治疗方法，用于将具有抗病原性的蛋白质靶向内小体和溶酶体。鉴于大多数已知的病原体通过内吞途径进入细胞的内小体和溶酶体，我们的方法可能是有用的，以摧毁这些间隔内的病原体。因此，本研究可能建立一个概念验证，并为动物和人类的传染病提供替代治疗方法，但目前尚无治疗方法。

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.