Cabral C M, Choudhury P, Liu Y, Sifers R N
Cell and Molecular Biology Graduate Program, Departments of Pathology and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Biol Chem. 2000 Aug 11;275(32):25015-22. doi: 10.1074/jbc.M910172199.
In the early secretory pathway, a distinct set of processing enzymes and family of lectins facilitate the folding and quality control of newly synthesized glycoproteins. In this regard, we recently identified a mechanism in which processing by endoplasmic reticulum mannosidase I, which attenuates the removal of glucose from asparagine-linked oligosaccharides, sorts terminally misfolded alpha(1)-antitrypsin for proteasome-mediated degradation in response to its abrogated physical dissociation from calnexin (Liu, Y., Choudhury, P., Cabral, C., and Sifers, R. N. (1999) J. Biol. Chem. 274, 5861-5867). In the present study, we examined the quality control of genetic variant PI Z, which undergoes inappropriate polymerization following biosynthesis. Here we show that in stably transfected hepatoma cells the additional processing of asparagine-linked oligosaccharides by endoplasmic reticulum mannosidase II partitions variant PI Z away from the conventional disposal mechanism in response to an arrested posttranslational interaction with calnexin. Intracellular disposal is accomplished by a nonproteasomal system that functions independently of cytosolic components but is sensitive to tyrosine phosphatase inhibition. The functional role of ER mannosidase II in glycoprotein quality control is discussed.
在早期分泌途径中，一组独特的加工酶和凝集素家族有助于新合成糖蛋白的折叠和质量控制。在这方面，我们最近发现了一种机制，即内质网甘露糖苷酶I的加工过程会减弱天冬酰胺连接寡糖上葡萄糖的去除，从而将最终错误折叠的α1抗胰蛋白酶分选出来，以便在其与钙连蛋白的物理解离被消除时，通过蛋白酶体介导进行降解（刘，Y.，乔杜里，P.，卡布拉尔，C.，和西弗斯，R.N.（1999年）《生物化学杂志》274，5861 - 5867）。在本研究中，我们研究了遗传变异体PI Z的质量控制，该变异体在生物合成后会发生不适当的聚合。在这里我们表明，在内质网甘露糖苷酶II对天冬酰胺连接寡糖进行额外加工的稳定转染肝癌细胞中，变异体PI Z会因与钙连蛋白的翻译后相互作用受阻而偏离传统的处理机制。细胞内的处理是由一个非蛋白酶体系统完成的，该系统独立于胞质成分发挥作用，但对酪氨酸磷酸酶抑制敏感。本文讨论了内质网甘露糖苷酶II在糖蛋白质量控制中的功能作用。
