Regulation of Lamp2a levels in the lysosomal membrane
Regulation of Lamp2a levels in the lysosomal membrane
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DOI：
10.1034/j.1600-0854.2000.010707.x
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发表时间：
2000-07-01
期刊：
影响因子：
4.5
通讯作者：
Dice, JF
中科院分区：
文献类型：
--
作者：
Cuervo, AM;Dice, JF
通过分子伴侣介导的自噬选择性降解溶酶体中的胞质蛋白，至少部分依赖于溶酶体膜上底物受体的释放。我们以前已经确定这种受体作为溶酶体相关膜蛋白2a型（lamp2a），并表明lamp2a在溶酶体膜的水平直接与蛋白水解途径的活性相关。在这里，我们表明，lamp2a在溶酶体膜的水平主要是由其半衰期的变化和溶酶体膜和基质之间的分布控制。lamp2a的溶酶体降解需要溶酶体膜上至少两种不同蛋白水解活性的组合作用。Lamp2a通过这些蛋白酶的作用从膜释放，然后截短的Lamp2a在溶酶体基质内迅速降解。lamp2a的膜降解是一个受调控的过程，在分子伴侣介导的自噬底物存在下以及在激活该类型自噬的条件下，该过程被抑制。底物蛋白的摄取也导致一些完整的lamp2a从溶酶体膜转运到基质中。lamp2a的这一部分可以重新插入到溶酶体膜中。lamp2a通过溶酶体基质的运输不是由囊泡介导的，并且lamp2a的重新插入需要溶酶体膜电位和溶酶体膜的蛋白组分。lamp2a在溶酶体膜和基质之间的分布是一个动态过程，其有助于lamp2a的溶酶体膜水平的调节，并因此有助于分子伴侣介导的自噬途径的活性。
The selective degradation of cytosolic proteins in lysosomes by chaperone-mediated autophagy depends, at least in part, on the revels of a substrate receptor at the lysosomal membrane. We have previously identified this receptor as the lysosome-associated membrane protein type 2a (lamp2a) and showed that levels of lamp2a at the lysosomal membrane directly correlate with the activity of the proteolytic pathway. Here we show that levels of lamp2a at the lysosomal membrane are mainly controlled by changes in its half-life and its distribution between the lysosomal membrane and the matrix. The lysosomal degradation of lamp2a requires the combined action of at least two different proteolytic activities at the lysosomal membrane. Lamp2a is released from the membrane by the action of these proteases, and then the truncated lamp2a is rapidly degraded within the lysosomal matrix. Membrane degradation of lamp2a is a regulated process that is inhibited in the presence of substrates for chaperone-mediated autophagy and under conditions that activate that type of autophagy. Uptake of substrate proteins also results in transport of some intact lamp2a from the lysosomal membrane into the matrix. This fraction of lamp2a can be reinserted back into the lysosomal membrane. The traffic of lamp2a through the lysosomal matrix is not mediated by vesicles, and lamp2a reinsertion requires the lysosomal membrane potential and protein components of the lysosomal membrane. The distribution of lamp2a between the lysosomal membrane and matrix is a dynamic process that contributes to the regulation of lysosomal membrane levels of lamp2a and consequently to the activity of the chaperone-mediated autophagic pathway.