Lysosome membrane lipid microdomains: novel regulators of chaperone-mediated autophagy
Lysosome membrane lipid microdomains: novel regulators of chaperone-mediated autophagy
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DOI：
10.1038/sj.emboj.7601283
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发表时间：
2006-09-06
期刊：
影响因子：
11.4
通讯作者：
Cuervo, Ana Maria
中科院分区：
文献类型：
--
作者：
Kaushik, Susmita;Massey, Ashish C.;Cuervo, Ana Maria
伴侣介导的自噬（CMA）是溶酶体中可溶性胞质蛋白降解的一种选择性机制。这种自噬的限制步骤是底物与溶酶体相关膜蛋白2A （LAMP-2A）的结合。在这项工作中，我们确定了溶酶体膜中LAMP-2A的动态亚区隔化，这是在CMA中调节LAMP-2A功能的分子基础。在休息条件下，一定比例的LAMP-2A定位于分离的溶酶体膜区域，但在CMA激活期间，它退出这些区域。通过胆固醇消耗剂破坏这些区域或表达排除这些区域的突变LAMP-2A可增强CMA活性，而装载胆固醇的溶酶体可显著降低CMA。通过CMA将底物转运到溶酶体所需的LAMP-2A组织成多聚体复合物，仅发生在富含脂质的膜微域外，而位于这些区域的LAMP-2A易受蛋白水解裂解和降解的影响。我们的研究结果支持LAMP-2A进出溶酶体膜离散微域的动态分布变化有助于调节CMA。
Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins in lysosomes. The limiting step of this type of autophagy is the binding of substrates to the lysosome-associated membrane protein type 2A (LAMP-2A). In this work, we identify a dynamic subcompartmentalization of LAMP-2A in the lysosomal membrane, which underlies the molecular basis for the regulation of LAMP-2A function in CMA. A percentage of LAMP-2A localizes in discrete lysosomal membrane regions during resting conditions, but it exits these regions during CMA activation. Disruption of these regions by cholesterol-depleting agents or expression of a mutant LAMP-2A excluded from these regions enhances CMA activity, whereas loading of lysosomes with cholesterol significantly reduces CMA. Organization of LAMP-2A into multimeric complexes, required for translocation of substrates into lysosomes via CMA, only occurs outside the lipid-enriched membrane microdomains, whereas the LAMP-2A located within these regions is susceptible to proteolytic cleavage and degradation. Our results support that changes in the dynamic distribution of LAMP-2A into and out of discrete microdomains of the lysosomal membrane contribute to regulate CMA.