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Cell pathology in lysosomal storage diseases is characterized by the formation of distended vacuoles with characteristics of lysosomes. Our previous studies in mucopolysaccharidosis type IIIB (MPSIIIB), a disease in which a genetic defect induces the accumulation of undigested heparan sulfate (HS) fragments, led to the hypothesis that abnormal lysosome formation was related to events occurring at the Golgi level. We reproduced the enzyme defect of MPSIIIB in HeLa cells using tetracycline-inducible expression of shRNAs directed against α-N-acetylglucosaminidase (NAGLU) and addressed this hypothesis. HeLa cells deprived of NAGLU accumulated abnormal lysosomes. The Golgi matrix protein GM130 was over-expressed. The cis- and medial-Golgi compartments were distended, elongated and formed circularized ribbons. The Golgi microtubule network was enlarged with increased amounts of AKAP450, a partner of GM130 controlling this network. GM130 down-regulation prevented pathology in HeLa cells deprived of NAGLU, whereas GM130 over-expression in control HeLa cells mimicked the pathology of deprived cells. We concluded that abnormal lysosomes forming in cells accumulating HS fragments were the consequence of GM130 gain-of-function and subsequent alterations of the Golgi ribbon architecture. These results indicate that GM130 functions are modulated by HS glycosaminoglycans and therefore possibly controlled by extracellular cues.

GM130 gain-of-function induces cell pathology in a model of lysosomal storage disease