Babst M, Odorizzi G, Estepa E J, Emr S D
Division of Cellular and Molecular Medicine and Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, La Jolla, CA 92093-0668, USA.
Traffic. 2000 Mar;1(3):248-58. doi: 10.1034/j.1600-0854.2000.010307.x.
The mammalian tumor susceptibility gene tsg101 encodes the homologue of Vps23p, a class E Vps protein essential for normal membrane trafficking in the late endosome/multivesicular body of yeast. Both proteins assemble into large (approximately 350 kDa) cytosolic protein complexes and we show that the yeast complex contains another class E Vps protein, Vps28p. tsg101 mutant cells exhibit defects in sorting and proteolytic maturation of the lysosomal hydrolase cathepsin D, as well as in the steady-state distribution of the mannose-6-phosphate receptor. Additionally, endocytosed EGF receptors that are normally sorted to the lysosome are instead rapidly recycled back to the cell surface in tsg101 mutant cells. We propose that tsg101 mutant cells are defective in the delivery of cargo proteins to late endosomal compartments. One consequence of this endosomal trafficking defect is the delayed down-regulation/degradation of activated cell surface receptors, resulting in prolonged signaling. This may contribute to the tumorigenic phenotype exhibited by the tsg101 mutant fibroblasts.
哺乳动物肿瘤易感基因tsg101编码Vps23p的同源物，Vps23p是一种E类Vps蛋白，对酵母晚期内体/多囊泡体中的正常膜运输至关重要。这两种蛋白质都组装成大型（约350 kDa）胞质蛋白复合物，并且我们发现酵母复合物含有另一种E类Vps蛋白Vps28p。tsg101突变细胞在溶酶体水解酶组织蛋白酶D的分选和蛋白水解成熟以及甘露糖-6-磷酸受体的稳态分布方面表现出缺陷。此外，正常情况下被分选到溶酶体的内吞表皮生长因子受体在tsg101突变细胞中反而迅速循环回到细胞表面。我们提出tsg101突变细胞在将货物蛋白递送至晚期内体区室方面存在缺陷。这种内体运输缺陷的一个后果是活化的细胞表面受体的下调/降解延迟，导致信号传导延长。这可能有助于tsg101突变成纤维细胞表现出的致瘤表型。
