Roles of CUP-5, the Caenorhabditis elegans orthologue of human TRPML1, in lysosome and gut granule biogenesis.
Roles of CUP-5, the Caenorhabditis elegans orthologue of human TRPML1, in lysosome and gut granule biogenesis.
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DOI：
10.1186/1471-2121-11-40
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发表时间：
2010-06-11
期刊：
影响因子：
--
通讯作者：
Fares H
中科院分区：
文献类型：
--
作者：
Campbell EM;Fares H
CUP-5是C.哺乳动物TRPML 1的直系同源物。TRPML 1的缺失导致溶酶体贮积症IV型粘脂沉积症。CUP-5的缺失导致胚胎死亡和发育中的肠细胞中增大的卵黄颗粒的积累。cup-5突变体的胚胎致死性被mrp-4突变所拯救，mrp-4是肠颗粒分化所必需的。肠道颗粒是积累双折射物质的丝氨酸特异性溶酶体相关细胞器。CUP-5和肠颗粒之间的这种联系使我们确定了CUP-5在发育中的肠细胞中的溶酶体和肠颗粒生物发生中的作用。我们发现，CUP-5蛋白定位于溶酶体，但不是肠颗粒，在发展中的肠细胞。CUP-5的缺失导致发育中的C.线虫胚胎这最终导致出现扩大的终末空泡，其显示有缺陷的溶酶体降解并具有溶酶体和内体标记物。相反，在不存在CUP-5的情况下，肠颗粒生物发生是正常的。此外，CUP-5的丢失不会导致溶酶体和肠颗粒之间的内容物的不适当融合或混合。使用MLIV的体内模型，我们发现，有一个缺陷，在溶酶体运输/生物发生，是早于推测的功能TRPML 1在终端溶酶体。我们的研究结果表明，CUP-5是必需的溶酶体的生物合成，但不是肠道颗粒。因此，IV型粘脂沉积症的细胞表型可能不是由于溶酶体相关细胞器生物发生缺陷，而是由于溶酶体转运进行性缺陷导致严重溶酶体功能障碍。
CUP-5 is a Transient Receptor Potential protein in C. elegans that is the orthologue of mammalian TRPML1. Loss of TRPML1 results in the lysosomal storage disorder Mucolipidosis type IV. Loss of CUP-5 results in embryonic lethality and the accumulation of enlarged yolk granules in developing intestinal cells. The embryonic lethality of cup-5 mutants is rescued by mutations in mrp-4, which is required for gut granule differentiation. Gut granules are intestine-specific lysosome-related organelles that accumulate birefringent material. This link between CUP-5 and gut granules led us to determine the roles of CUP-5 in lysosome and gut granule biogenesis in developing intestinal cells. We show that CUP-5 protein localizes to lysosomes, but not to gut granules, in developing intestinal cells. Loss of CUP-5 results in defects in endo-lysosomal transport in developing intestinal cells of C. elegans embryos. This ultimately leads to the appearance of enlarged terminal vacuoles that show defective lysosomal degradation and that have lysosomal and endosomal markers. In contrast, gut granule biogenesis is normal in the absence of CUP-5. Furthermore, loss of CUP-5 does not result in inappropriate fusion or mixing of content between lysosomes and gut granules. Using an in vivo model of MLIV, we show that there is a defect in lysosomal transport/biogenesis that is earlier than the presumed function of TRPML1 in terminal lysosomes. Our results indicate that CUP-5 is required for the biogenesis of lysosomes but not of gut granules. Thus, cellular phenotypes in Mucolipidosis type IV are likely not due to defects in lysosome-related organelle biogenesis, but due to progressive defects in lysosomal transport that lead to severe lysosomal dysfunction.
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