Molecular and cellular basis of lysosomal transmembrane protein dysfunction
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- 作者：Raquel Ruivo ; Christine Anne ; Corinne Sagné ; Bruno Gasnier
- 关键词：Lysosomal storage disorder ; Lysosomal membrane ; Transporter ; Channel ; Cystinosis ; Salla disease ; Infantile sialic acid disorder ; Cobalamin F type disease ; Mucopolysaccharidosis ; Sanfilippo C syndrome ; Osteopetrosis ; Mucolipidosis type IV ; Danon disease ; C
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：2009
- 出版时间：April 2009
- 年：2009
- 卷：1793
- 期：4
- 页码：636-649
- 全文大小：619 K
文摘
Lysosomal membrane proteins act at several crucial steps of the lysosome life cycle, including lumen acidification, metabolite export, molecular motor recruitment and fusion with other organelles. This review summarizes the molecular mechanisms of lysosomal storage diseases caused by defective transport of small molecules or ions across the lysosomal membrane, as well as Danon disease. In cystinosis and free sialic acid storage diseases, transporters for cystine and acidic monosaccharides, respectively, are blocked or retarded. A putative cobalamin transporter and a hybrid transporter/transferase of acetyl groups are defective in cobalamin F type disease and mucopolysaccharidosis type IIIC, respectively. In neurodegenerative forms of osteopetrosis, mutations of a proton/chloride exchanger impair the charge balance required for sustained proton pumping by the V-type ATPase, thus resulting in bone-resorption lacuna neutralization. However, the mechanism leading to lysosomal storage and neurodegeneration remains unclear. Mucolipidosis type IV is caused by mutations of a lysosomal cation channel named TRPML1; its gating properties are still poorly understood and the ion species linking this channel to lipid storage and membrane traffic defects is debated. Finally, the autophagy defect of Danon disease apparently arises from a role of LAMP2 in lysosome/autophagosome fusion, possibly secondary to a role in dynein-based centripetal motility.