The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane
The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane
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DOI：
10.1128/mcb.02070-07
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发表时间：
2008-09-01
影响因子：
5.3
通讯作者：
Cuervo, Ana Maria
中科院分区：
文献类型：
--
作者：
Bandyopadhyay, Urmi;Kaushik, Susmita;Cuervo, Ana Maria
分子伴侣介导的自噬（CMA）是一种选择性的自噬类型，通过这种自噬，特定的细胞溶质蛋白被送到溶酶体进行降解。底物蛋白通过溶酶体相关膜蛋白2A型（LAMP-2A）（lamp 2基因的三种剪接变体之一）与溶酶体膜结合，这种结合限制了它们通过CMA的降解。然而，底物结合和摄取的机制仍然未知。我们在这里报告，LAMP-2A在溶酶体膜组织成不同大小的蛋白质复合物。这些复合物的组装和分解是一个非常动态的过程，与CMA活性直接相关。底物蛋白仅与单体LAMP-2A结合，而底物的有效转运需要形成特定的高分子量LAMP-2A复合物。与CMA相关的两种主要分子伴侣hsc 70和hsp 90在溶酶体膜上的LAMP-2A复合物的功能动力学中起关键作用。因此，我们已经确定了一种新的功能，hsc 70在拆卸的LAMP-2A从这些复合物，而溶酶体相关的热休克蛋白90的存在是必不可少的，以保持稳定的LAMP-2A在溶酶体膜。
Chaperone-mediated autophagy (CMA) is a selective type of autophagy by which specific cytosolic proteins are sent to lysosomes for degradation. Substrate proteins bind to the lysosomal membrane through the lysosome-associated membrane protein type 2A (LAMP-2A), one of the three splice variants of the lamp2 gene, and this binding is limiting for their degradation via CMA. However, the mechanisms of substrate binding and uptake remain unknown. We report here that LAMP-2A organizes at the lysosomal membrane into protein complexes of different sizes. The assembly and disassembly of these complexes are a very dynamic process directly related to CMA activity. Substrate proteins only bind to monomeric LAMP-2A, while the efficient translocation of substrates requires the formation of a particular high-molecular-weight LAMP-2A complex. The two major chaperones related to CMA, hsc70 and hsp90, play critical roles in the functional dynamics of the LAMP-2A complexes at the lysosomal membrane. Thus, we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes, whereas the presence of lysosome-associated hsp90 is essential to preserve the stability of LAMP-2A at the lysosomal membrane.