REGULATION OF ALPHA-L-FUCOSIDASE IN HEALTH AND DISEASE

新合成酶和水解酶的准确传递

The accurate delivery of newly synthesized and hydrolases from the rough endoplasmic reticulum to residency in lysosomes or extracellular fluids involves a series of co- and post-translational modifications of the protein and carbohydrate moieties of these enzymes. The phosphomannosyl recognition system is an important mechanism for directing newly synthesized acid hydrolases to lysosomes. The essence of this system is the acquisition of phosphomannosyl residues by acid hydrolases, which leads to binding to specific membrane-bound transport receptors and delivery to lysosomes. However, there is considerable evidence suggesting alternate pathways for targeting acid hydrolases, including alpha-L-fucosidase. This proposal will test the hypothesis that the delivery of newly made alpha-L- fucosidase to lysosomes in lymphoid cells is mediated by phosphomannosyl dependent and independent pathways. The broad objectives are to determine molecular requirements for routing of alpha-L-fucosidase in lymphoid cells and to determine the molecular basis of the defects in the trafficking of alpha-L-fucosidase in lymphoid cell lines derived from fucosidosis and I- cell disease patients. Specific objectives are to research 1) the phosphorylation of alpha-L-fucosidase, 2) the type and content of phosphomannosyl receptors, 3) the subcellular localization of alpha-L- fucosidase, and 4) the precise nature of mutations causing fucosidosis and abnormal secretion of alpha-L-fucosidase. These investigations should provide 1) information concerning requirements for trafficking of alpha-L- fucosidosis and I-cell disease, 3) information about alternative mechanisms for trafficking of acid hydrolases. These experiments could provide a rational basis for treatment of disease.