Accumulation of the insoluble PiZ variant of human alpha 1-antitrypsin within the hepatic endoplasmic reticulum does not elevate the steady-state level of grp78/BiP.
Accumulation of the insoluble PiZ variant of human alpha 1-antitrypsin within the hepatic endoplasmic reticulum does not elevate the steady-state level of grp78/BiP.
复制标题
人α1-抗胰蛋白酶的不溶性PiZ变体在肝内质网内的积累不会提高grp78/BiP的稳态水平。
DOI：
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发表时间：
1990
影响因子：
4.8
通讯作者：
R. Sifers
中科院分区：
文献类型：
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作者：
K. S. Graham;A. Le;R. Sifers
超过85%的转运受损的人α1-抗胰蛋白酶的PIZ变体保留在细胞内，随后在高尔基体前非溶酶体隔室中降解，该隔室显然与内质网(ER)分开(Le，A.，Graham，K.S.和Sifers，R.N.(1990)J.Biol)。化学。265、14001-14007)。尽管有这种现象，人类患者和携带PIZ的转基因小鼠显示出未降解的蛋白质在肝脏ER膨胀的脑池内以不可溶聚集体的形式积累(Carlson，J.A.，Rogers，B.B.，Sifers，R.N.，Finegold，M.J.，Clip，S.M.，DeMayo，F.J.，Bullock，D.W.和Woo，S.L.C.()J.Clin)。投资。83、1183-1190)。从转基因动物的脉冲放射性标记的肝细胞中进行的PIZ变体的免疫沉淀表明，新合成的微量突变蛋白显然对降解具有抵抗力，并逐渐在细胞的颗粒部分积累。尽管驻留的ER蛋白GRP78/Bip的稳定水平随着错误折叠蛋白在该亚细胞内的积累而升高，但这种现象并不是由不溶性PIZ变体的积累引起的。这些结果表明，无论是这种错误折叠的蛋白质在内质网内的积累，甚至是亚细胞室的扩张，都不足以导致GRP78/Bip水平的上调。关于调节内质网中GRP78/Bip水平的因素，对这些结果的解释进行了讨论。
Greater than 85% of the transport-impaired PiZ variant of human alpha 1-antitrypsin is retained within cells and subsequently degraded within a pre-Golgi nonlysosomal compartment that is apparently separate from the endoplasmic reticulum (ER) (Le, A., Graham, K. S., and Sifers, R. N. (1990) J. Biol. Chem. 265, 14001-14007). Despite this phenomenon, human patients and PiZ-bearing transgenic mice exhibit an accumulation of the undegraded protein as insoluble aggregates within distended cisternae of the hepatic ER (Carlson, J. A., Rogers, B. B., Sifers, R. N., Finegold, M. J., Clift, S. M., DeMayo, F. J., Bullock, D. W., and Woo, S. L. C. (1989) J. Clin. Invest. 83, 1183-1190). Immunoprecipitation of the PiZ variant from pulse-radiolabeled hepatocytes from the transgenic animals has demonstrated that a minute quantity of the newly synthesized mutant protein is apparently resistant to degradation and accumulates gradually within the particulate fraction of the cell. Although the steady-state level of the resident ER protein grp78/BiP is elevated in response to the accumulation of malfolded proteins within that subcellular compartment, this phenomenon is not elicited by the accumulation of the insoluble PiZ variant. These results indicate that neither the accumulation of this malfolded protein within the ER nor even the distention of that subcellular compartment is sufficient to cause the up-regulation of grp78/BiP levels. The interpretation of these results with regard to the factors that regulate the levels of grp78/BiP in the ER is discussed.