Cathepsin A regulates chaperone-mediated autophagy through cleavage of the lysosomal receptor
Cathepsin A regulates chaperone-mediated autophagy through cleavage of the lysosomal receptor
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DOI：
10.1093/emboj/cdg002
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发表时间：
2003-01-02
期刊：
影响因子：
11.4
通讯作者：
Dice, JF
中科院分区：
文献类型：
--
作者：
Cuervo, AM;Mann, L;Dice, JF
保护蛋白/组织蛋白酶A（PPCA）具有丝氨酸羧肽酶活性，其生理功能未知。我们现在证明，这种蛋白酶活性触发溶酶体相关膜蛋白2a型（lamp 2a），伴侣介导的自噬（CMA）的受体的降解。lamp 2a的降解是重要的，因为其在溶酶体膜中的水平是CMA的限速步骤。PPCA缺陷的细胞显示lamp 2a降解速率降低、lamp 2a水平升高和CMA速率升高。PPCA蛋白酶活性的恢复增加lamp 2a降解速率，降低溶酶体lamp 2a水平并降低CMA速率。PPCA与溶酶体膜上的lamp 2a结合，并在腔结构域和跨膜结构域之间的边界附近切割lamp 2a。除了PPCA在靶向和保护两种溶酶体糖基化酶中的充分研究的作用外，我们还定义了这种多功能蛋白的蛋白水解活性的作用。
Protective protein/cathepsin A (PPCA) has a serine carboxypeptidase activity of unknown physiological function. We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA). Degradation of lamp2a is important because its level in the lysosomal membrane is a rate-limiting step of CMA. Cells defective in PPCA show reduced rates of lamp2a degradation, higher levels of lamp2a and higher rates of CMA. Restoration of PPCA protease activity increases rates of lamp2a degradation, reduces levels of lysosomal lamp2a and reduces rates of CMA. PPCA associates with lamp2a on the lysosomal membrane and cleaves lamp2a near the boundary between the luminal and transmembrane domains. In addition to the well-studied role of PPCA in targeting and protecting two lysosomal glycosidases, we have defined a role for the proteolytic activity of this multifunctional protein.