Department of Development and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mol Cell. 2010 Aug 27;39(4):535-47. doi: 10.1016/j.molcel.2010.08.004.
Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of cytosolic proteins in lysosomes that contributes to cellular quality control and becomes an additional source of amino acids when nutrients are scarce. A chaperone complex delivers CMA substrates to a receptor protein at the lysosomal membrane that assembles into multimeric translocation complexes. However, the mechanisms regulating this process remain, for the most part, unknown. In this work, we have identified two regulatory proteins, GFAP and EF1alpha, that mediate a previously unknown inhibitory effect of GTP on CMA. GFAP stabilizes the multimeric translocation complex against chaperone-mediated disassembly, whereas GTP-mediated release of EF1alpha from the lysosomal membrane promotes self-association of GFAP, disassembly of the CMA translocation complex, and the consequent decrease in CMA. The dynamic interactions of these two proteins at the lysosomal membrane unveil now a role for GTP as a negative regulator of CMA.
伴侣蛋白介导的自噬（CMA）是溶酶体中降解细胞质蛋白的一种选择性机制，有助于细胞质量控制，并且在营养物质匮乏时成为氨基酸的额外来源。伴侣蛋白复合物将 CMA 底物递送到溶酶体膜上的受体蛋白，该受体蛋白组装成多聚体转运复合物。然而，调节这一过程的机制在很大程度上仍然未知。在这项工作中，我们已经确定了两种调节蛋白，GFAP 和 EF1alpha，它们介导了 GTP 对 CMA 的先前未知的抑制作用。GFAP 稳定多聚体转运复合物，防止伴侣蛋白介导的解体，而 GTP 介导的 EF1alpha 从溶酶体膜上释放则促进 GFAP 的自缔合、CMA 转运复合物的解体以及随后 CMA 的减少。这两种蛋白质在溶酶体膜上的动态相互作用揭示了 GTP 作为 CMA 的负调节剂的作用。
