Role for phosphatidylinositol 3-kinase in the sorting and transport of newly synthesized lysosomal enzymes in mammalian cells.
Role for phosphatidylinositol 3-kinase in the sorting and transport of newly synthesized lysosomal enzymes in mammalian cells.
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磷脂酰肌醇3-激酶在哺乳动物细胞中新合成溶酶体酶的分选和转运中的作用。
DOI：
10.1083/jcb.130.4.781
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发表时间：
1995-08
影响因子：
7.8
通讯作者：
BALCH, WE
中科院分区：
文献类型：
--
作者：
BROWN, WJ;DEWALD, DB;EMR, SD;PLUTNER, H;BALCH, WE
先前对酵母酿酒酵母（Saccharomycescerevisiae）的工作已经证明了磷脂酰肌醇特异性PI 3-激酶（VPS 34基因的产物）在将新合成的蛋白质靶向空泡（一种功能上等同于哺乳动物溶酶体的细胞器）中的作用（Schu，P. V.，K. Takegawa，M. J. Fry，J. H.斯塔克，M. D. Waterfield和S. D. Emr. 1993.科学（Wash）DC]。260：88-91）。Vps 34 p激酶的活性被P13-激酶抑制剂渥曼青霉素（wortmannin）（一种真菌代谢物）和LY 294002（一种槲皮素类似物）显著降低（Stack，J.H.，和S. D. Emr. 1994. J.Biol.Chem.269：31552-31562）。我们在这里表明，在抑制VPS 34编码的PI 3-激酶活性的浓度下，渥曼青霉素也抑制新合成的组织蛋白酶D的加工和递送至哺乳动物细胞中的溶酶体，其中递送的半数最大抑制发生在100 nM渥曼青霉素。作为渥曼青霉素作用的结果，新合成的未加工的组织蛋白酶D分泌到培养基中。此外，在20 ℃下在反式高尔基体网络（TGN）中积累后，在加入渥曼青霉素并转移到37 ℃后，组织蛋白酶D迅速错配到分泌途径中.在抑制溶酶体酶递送的浓度下，渥曼青霉素和LY 294002均引起前溶酶体隔室（PLC）的富含甘露糖6-磷酸受体（M6 PR）的囊泡的高度特异性扩张，所述囊泡在处理后15分钟内膨胀至约1微米。随着时间的增加，抑制剂引起M6 PR分布的显著但可逆的变化。由3小时的治疗，肿胀PLC空泡基本上耗尽的受体，此外，有一个四倍的损失，从细胞表面的受体。然而，TGN中M6 PR仍然丰富。这些结果与PI 3-激酶通过干扰TGN中的M6 PR依赖性分选事件来调节溶酶体酶的运输的解释最一致。此外，他们提供的证据表明，运输可溶性水解酶的哺乳动物溶酶体和酵母液泡依赖于类似的监管机制。
Previous work with the yeast Saccharomyces cerevisiae has demonstrated a role for a phosphatidylinositol-specific PI 3-kinase, the product of the VPS34 gene, in the targeting of newly synthesized proteins to the vacuole, an organelle functionally equivalent to mammalian lysosomes (Schu, P. V., K. Takegawa, M. J. Fry, J. H. Stack, M. D. Waterfield, and S. D. Emr. 1993. Science [Wash. DC]. 260:88-91). The activity of Vps34p kinase is significantly reduced by the PI 3-kinase inhibitors wortmannin, a fungal metabolite, and LY294002, a quercetin analog (Stack, J. H., and S. D. Emr. 1994. J. Biol. Chem. 269:31552-31562). We show here that at concentrations which inhibit VPS34-encoded PI 3- kinase activity, wortmannin also inhibits the processing and delivery of newly synthesized cathepsin D to lysosomes in mammalian cells with half-maximal inhibition of delivery occurring at 100 nM wortmannin. As a result of wortmannin action, newly synthesized, unprocessed cathepsin D is secreted into the media. Moreover, after accumulation in the trans- Golgi network (TGN) at 20 degrees C, cathepsin D was rapidly missorted to the secretory pathway after addition of wortmannin and shifting to 37 degrees C. At concentrations that inhibited lysosomal enzyme delivery, both wortmannin and LY294002 caused a highly specific dilation of mannose 6-phosphate receptor (M6PR)-enriched vesicles of the prelysosome compartment (PLC), which swelled to approximately 1 micron within 15 min after treatment. With increasing time, the inhibitors caused a significant yet reversible change in M6PR distribution. By 3 h of treatment, the swollen PLC vacuoles were essentially depleted of receptors and, in addition, there was a fourfold loss of receptors from the cell surface. However, M6PRs were still abundant in the TGN. These results are most consistent with the interpretation that PI 3-kinase regulates the trafficking of lysosomal enzymes by interfering with a M6PR-dependent sorting event in the TGN. Moreover, they provide evidence that trafficking of soluble hydrolases to mammalian lysosomes and yeast vacuoles rely on similar regulatory mechanisms.
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DOI：
10.1083/jcb.116.6.1343
发表时间：
1992-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Davidson HW;McGowan CH;Balch WE
通讯作者：
Balch WE
影响因子：
11.4
作者：
CARLBERG, K;TAPLEY, P;ROHRSCHNEIDER, L
通讯作者：
ROHRSCHNEIDER, L
影响因子：
5.3
作者：
CARPENTER, CL;AUGER, KR;CANTLEY, LC
通讯作者：
CANTLEY, LC
影响因子：
5.3
作者：
CHEATHAM, B;VLAHOS, CJ;KAHN, CR
通讯作者：
KAHN, CR
内吞囊泡中的甘露糖6-磷酸受体和溶酶体膜蛋白的分选。
影响因子：
7.8
作者：
Geuze, H J;Stoorvogel, W;Strous, G J;Slot, J W;Bleekemolen, J E;Mellman, I
通讯作者：
Mellman, I