Treusch Sebastian, Knuth Sarah, Slaugenhaupt Susan A, Goldin Ehud, Grant Barth D, Fares Hanna
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4483-8. doi: 10.1073/pnas.0400709101. Epub 2004 Mar 15.
Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disease characterized by severe psychomotor retardation, achlorhydria, and ophthalmological abnormalities. Cells from several tissues in MLIV patients accumulate large vacuoles that are presumed to be lysosomes, but whose exact nature remains to be determined. Other defects include the deterioration of neuronal integrity in the retina and the cerebellum. MCOLN1, the gene mutated in MLIV patients, encodes a protein called h-mucolipin-1 that has six predicted transmembrane domains and functions as a Ca(2+)-permeable channel that is modulated by changes in Ca2+ concentration. CUP-5 is the Caenorhabditis elegans functional orthologue of h-mucolipin-1. Mutations in cup-5 result in the accumulation of large vacuoles in several cells, in increased cell death, and in embryonic lethality. We demonstrate here that CUP-5 functions in the biogenesis of lysosomes originating from hybrid organelles. We also show that at least two h-mucolipin family members rescue cup-5 mutant endocytic defects, indicating that there may be functional redundancy among the human proteins. Finally, we propose a model that relates the lysosome biogenesis defect in the absence of CUP-5/h-mucolipin-1 to cellular phenotypes in worms and in humans.
IV型粘脂贮积症（MLIV）是一种常染色体隐性溶酶体贮积病，其特征为严重的精神运动发育迟缓、胃酸缺乏和眼科异常。MLIV患者多个组织的细胞会积累大量空泡，这些空泡被认为是溶酶体，但其确切性质仍有待确定。其他缺陷包括视网膜和小脑中神经元完整性的恶化。MCOLN1是MLIV患者中发生突变的基因，编码一种名为h-粘脂蛋白-1的蛋白质，该蛋白质有六个预测的跨膜结构域，作为一种Ca(2+)可渗透通道发挥作用，其功能受Ca2+浓度变化的调节。CUP-5是h-粘脂蛋白-1在秀丽隐杆线虫中的功能同源物。cup-5突变会导致多个细胞中出现大量空泡积累、细胞死亡增加以及胚胎致死。我们在此证明，CUP-5在源自混合细胞器的溶酶体生物合成中发挥作用。我们还表明，至少两个h-粘脂蛋白家族成员可挽救cup-5突变体的内吞缺陷，这表明人类蛋白质之间可能存在功能冗余。最后，我们提出了一个模型，将缺乏CUP-5/h-粘脂蛋白-1时的溶酶体生物合成缺陷与线虫和人类的细胞表型联系起来。
