Novel strategy to intercept pathogens at the site of cellular entry

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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.