Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy.
Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy.
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DOI：
10.1016/j.molcel.2015.05.030
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发表时间：
2015-07-16
期刊：
影响因子：
16
通讯作者：
Cuervo AM
中科院分区：
文献类型：
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作者：
Arias E;Koga H;Diaz A;Mocholi E;Patel B;Cuervo AM
分子伴侣介导的自噬（CMA）是溶酶体中胞浆蛋白降解的一种选择性形式，有助于维持蛋白质稳态和细胞对应激的适应。CMA底物通过胞质分子伴侣递送至溶酶体表面，在那里展开后，通过膜易位复合物内化。参与CMA底物靶向和转运的分子组分已得到很好的表征，但参与CMA调节的分子组分仍大部分未知。在这项研究中，我们已经确定CMA是在磷酸酶PHLPP 1的阳性控制下，该磷酸酶与溶酶体膜结合并抵消mTORC 2对CMA的抑制作用。溶酶体Akt是mTORC 2/PHLPP 1激酶-磷酸酶对的靶点，通过控制CMA易位复合物在溶酶体膜上组装和分解的动力学来调节CMA活性。溶酶体mTORC 2/PHLPP 1/Akt轴可能成为恢复衰老和疾病中CMA功能障碍的靶点。
Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are delivered by a cytosolic chaperone to the lysosomal surface, where upon unfolding, are internalized through a membrane translocation complex. The molecular components that participate in CMA substrate targeting and translocation are well characterized but those involved in CMA regulation remain mostly unknown. In this study, we have identified that CMA is under the positive control of the phosphatase PHLPP1 that associates with the lysosomal membrane and counteracts the inhibitory effect of mTORC2 on CMA. Lysosomal Akt, a target of the mTORC2/PHLPP1 kinase-phosphatase pair, modulates CMA activity by controlling the dynamics of assembly and disassembly of the CMA translocation complex at the lysosomal membrane. The lysosomal mTORC2/PHLPP1/Akt axis could become a target to restore CMA dysfunction in aging and disease.