IκB is a substrate for a selective pathway of lysosomal proteolysis
IκB is a substrate for a selective pathway of lysosomal proteolysis
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DOI：
10.1091/mbc.9.8.1995
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发表时间：
1998-08-01
影响因子：
3.3
通讯作者：
Dice, JF
中科院分区：
文献类型：
--
作者：
Cuervo, AM;Hu, W;Dice, JF
在从大鼠肝脏和脾脏分离的溶酶体中，可以在溶酶体基质中检测到一定百分比的核因子κ B（I κ B）细胞内抑制剂，在溶酶体基质中，I κ B被快速降解。I κ B的水平在直接摄取特定胞质蛋白的溶酶体亚群中显著更高。I κ B在需要I κ B与73 kDa的热休克蛋白（hsc 73）（参与该途径的细胞溶质分子伴侣）和96 kDa的溶酶体糖蛋白（lgp 96）（溶酶体膜中的受体蛋白）结合的过程中直接转运到分离的溶酶体中。该降解途径的其他底物竞争性抑制I κ B被溶酶体摄取。I κ B的泛素化和磷酸化不是其靶向溶酶体所必需的。I κ B的溶酶体降解在营养剥夺条件下被激活。因此，在补充血清的中国仓鼠卵巢细胞中，I κ B的长寿命池的半衰期为4.4 d，但在缺乏血清的中国仓鼠卵巢细胞中仅为0.9 d。这种I κ B降解的增加可被溶酶体抑制剂完全阻断。在中国仓鼠卵巢细胞中，由于lamp2（lgp 96的人形式）的过表达而表现出hsc 73介导的溶酶体降解途径的活性增加，I κ B的降解增加。存在I κ B的短寿命池和长寿命池，并且经受选择性溶酶体降解途径的是长寿命池。在抗氧化剂的存在下，I κ B的长寿命池的半衰期显著增加。因此，在血清饥饿过程中细胞内活性氧的产生可能是介导I κ B降解的机制之一。I κ B的溶酶体降解的这种选择性途径在生理学上是重要的，因为长时间的血清剥夺导致核因子κ B的核活性增加。此外，当这种溶酶体蛋白水解途径被激活时，核因子κ B对几种刺激的反应增加。
In lysosomes isolated from rat liver and spleen, a percentage of the intracellular inhibitor of the nuclear factor kappa B (I kappa B) can be detected in the lysosomal matrix where it is rapidly degraded. Levels of I kappa B are significantly higher in a lysosomal subpopulation that is active in the direct uptake of specific cytosolic proteins. I kappa B is directly transported into isolated lysosomes in a process that requires binding of I kappa B to the heat shock protein of 73 kDa (hsc73), the cytosolic molecular chaperone involved in this pathway, and to the lysosomal glycoprotein of 96 kDa (lgp96), the receptor protein in the lysosomal membrane. Other substrates for this degradation pathway competitively inhibit I kappa B uptake by lysosomes. Ubiquitination and phosphorylation of I kappa B are not required for its targeting to lysosomes. The lysosomal degradation of I kappa B is activated under conditions of nutrient deprivation. Thus, the half-life of a long-lived pool of I kappa B is 4.4 d in serum-supplemented Chinese hamster ovary cells but only 0.9 d in serum-deprived Chinese hamster ovary cells. This increase in I kappa B degradation can be completely blocked by lysosomal inhibitors. In Chinese hamster ovary cells exhibiting an increased activity of the hsc73-mediated lysosomal degradation pathway due to overexpression of lamp2, the human form of lgp96, the degradation of I kappa B is increased. There are both short- and long-lived pools of I kappa B, and it is the long-lived pool that is subjected to the selective lysosomal degradation pathway. In the presence of antioxidants, the half-life of the long-lived pool of I kappa B is significantly increased. Thus, the production of intracellular reactive oxygen species during serum starvation may be one of the mechanisms mediating I kappa B degradation in lysosomes. This selective pathway of lysosomal degradation of I kappa B is physiologically important since prolonged serum deprivation results in an increase in the nuclear activity of nuclear factor kappa B. In addition, the response of nuclear factor kappa B to several stimuli increases when this lysosomal pathway of proteolysis is activated.