Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders
Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders
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DOI：
10.1038/emboj.2010.237
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发表时间：
2010-11-03
期刊：
影响因子：
11.4
通讯作者：
Ballabio, Andrea
中科院分区：
文献类型：
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作者：
Fraldi, Alessandro;Annunziata, Fabio;Ballabio, Andrea
溶酶体的功能依赖于溶酶体膜与细胞中多个靶膜融合的能力。众所周知，在溶酶体贮积症（LSD）中，几种底物的溶酶体积累与溶酶体功能障碍和内吞膜运输受损有关。通过分析两种严重神经退行性LSD的细胞，我们观察到胆固醇异常积聚在LSD细胞的溶酶体膜中，从而降低了溶酶体与内吞和自噬囊泡有效融合的能力。此外，我们发现可溶性N-乙基马来酰亚胺敏感因子附着蛋白（SNAP）受体（SNARE）是细胞膜融合机制的关键组成部分，被异常地隔离在LSD内溶酶体膜的富含胆固醇的区域中。这种异常的空间组织将 SNARE 锁定在复合体中，并损害它们的分类和回收。重要的是，降低 LSD 细胞中的膜胆固醇水平可以恢复正常的 SNARE 功能和有效的溶酶体融合。我们的结果支持了一个模型，通过该模型，胆固醇异常通过损害膜融合机制来决定LSD中的溶酶体功能障碍和内吞交通堵塞，从而为治疗这些疾病提出了新的治疗靶点。 EMBO 杂志 (2010) 29, 3607-3620。 doi：10.1038/emboj.2010.237； 2010 年 9 月 24 日在线发布
The function of lysosomes relies on the ability of the lysosomal membrane to fuse with several target membranes in the cell. It is known that in lysosomal storage disorders (LSDs), lysosomal accumulation of several types of substrates is associated with lysosomal dysfunction and impairment of endocytic membrane traffic. By analysing cells from two severe neurodegenerative LSDs, we observed that cholesterol abnormally accumulates in the endolysosomal membrane of LSD cells, thereby reducing the ability of lysosomes to efficiently fuse with endocytic and autophagic vesicles. Furthermore, we discovered that soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNAREs), which are key components of the cellular membrane fusion machinery are aberrantly sequestered in cholesterol-enriched regions of LSD endolysosomal membranes. This abnormal spatial organization locks SNAREs in complexes and impairs their sorting and recycling. Importantly, reducing membrane cholesterol levels in LSD cells restores normal SNARE function and efficient lysosomal fusion. Our results support a model by which cholesterol abnormalities determine lysosomal dysfunction and endocytic traffic jam in LSDs by impairing the membrane fusion machinery, thus suggesting new therapeutic targets for the treatment of these disorders. The EMBO Journal (2010) 29, 3607-3620. doi:10.1038/emboj.2010.237; Published online 24 September 2010