Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response.
Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response.
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发表时间：
2005
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通讯作者：
T. Hidvegi;Béla Z. Schmidt;P. Hale;D. Perlmutter
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作者：
T. Hidvegi;Béla Z. Schmidt;P. Hale;D. Perlmutter
在α(1)-抗胰蛋白酶(α1AT)缺乏症中，分泌型糖蛋白α1AT的多基因突变形式α1ATZ保留在肝细胞的内质网(ER)中。目前尚不清楚这如何导致一组缺陷个体的肝脏损伤，以及其余缺陷个体如何逃脱肝病。一种可能的解释是，“易感”亚群无法启动适当的保护性细胞反应。在这里，我们通过使用突变Alpha1AT可诱导表达的细胞系以及肝脏特异性诱导表达突变Alpha1AT的转基因小鼠的肝脏，研究了突变Alpha1ATZ对几个潜在的保护性信号通路的影响。结果表明，多基因突变体alpha1ATZ的内质网滞留不会导致未折叠蛋白反应(UPR)。衣霉素可以在α1ATZ存在的情况下诱导UPR，排除该通路已被禁用的可能性。与之形成鲜明对比的是，非聚合性α1AT突变体的内质网滞留确实诱导了UPR。这些结果表明，负责激活UPR的机制可以区分积累在内质网中的蛋白质的物理特征，从而使其能够对错误折叠但不是相对有序的聚合结构做出反应。突变的alpha1ATZ的积累确实激活了特定的信号通路，包括小鼠的caspase-12，人的caspase-4，NFkappaB和BAP31，这一谱不同于非聚合基因的alpha1AT突变体激活的谱。
In alpha(1)-antitrypsin (alpha1AT) deficiency, a polymerogenic mutant form of the secretory glycoprotein alpha1AT, alpha1ATZ, is retained in the endoplasmic reticulum (ER) of liver cells. It is not yet known how this results in liver injury in a subgroup of deficient individuals and how the remainder of deficient individuals escapes liver disease. One possible explanation is that the "susceptible" subgroup is unable to mount the appropriate protective cellular responses. Here we examined the effect of mutant alpha1ATZ on several potential protective signaling pathways by using cell lines with inducible expression of mutant alpha1AT as well as liver from transgenic mice with liver-specific inducible expression of mutant alpha1AT. The results show that ER retention of polymerogenic mutant alpha1ATZ does not result in an unfolded protein response (UPR). The UPR can be induced in the presence of alpha1ATZ by tunicamycin excluding the possibility that the pathway has been disabled. In striking contrast, ER retention of nonpolymerogenic alpha1AT mutants does induce the UPR. These results indicate that the machinery responsible for activation of the UPR can distinguish the physical characteristics of proteins that accumulate in the ER in such a way that it can respond to misfolded but not relatively ordered polymeric structures. Accumulation of mutant alpha1ATZ does activate specific signaling pathways, including caspase-12 in mouse, caspase-4 in human, NFkappaB, and BAP31, a profile that was distinct from that activated by nonpolymerogenic alpha1AT mutants.