Tipping the delicate balance - Defining how proteasome maturation affects the degradation of a substrate for autophagy and endoplasmic reticulum associated degradation (ERAD)
Tipping the delicate balance - Defining how proteasome maturation affects the degradation of a substrate for autophagy and endoplasmic reticulum associated degradation (ERAD)
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DOI：
10.4161/auto.4906
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发表时间：
2007-11-01
期刊：
影响因子：
13.3
通讯作者：
Scott, Craig M.
中科院分区：
文献类型：
--
作者：
Brodsky, Jeffrey L.;Scott, Craig M.
越来越多的数据将内质网（ER）功能与自噬联系起来。因此，毫不奇怪，ER中的一些异常蛋白可以通过蛋白酶体介导的ER相关降解（ERAD）或通过自噬被破坏。一种这样的底物是α-1蛋白酶抑制剂（A1 Pi）的“Z”变体，通常称为A1 Pi-Z或ATZ（“抗胰蛋白酶，Z变体”）。野生型蛋白主要在肝脏中合成并分泌。与此相反，AT-Z，像其他ERAD底物，从ER逆向易位并递送到蛋白酶体。然而，ATZ可以形成通过自噬降解的高分子量聚合物，并且积累ATZ聚合物的细胞最终屈服，这导致肝脏疾病。因此，鉴定影响ATZ周转的基因是一个活跃的研究领域。为此，ATZ的酵母表达系统已被证明是有价值的。例如，最近使用该系统的一项研究表明，蛋白酶体组装伴侣（PAC）的活性对最大ATZ周转至关重要，这表明PAC的新作用。由于PAC是保守的，因此分析这些专用分子伴侣是否与ERAD和自噬相关的其他疾病有关将是至关重要的。
An increasing body of data links endoplasmic reticulum (ER) function to autophagy. Not surprisingly, then, some aberrant proteins in the ER can be destroyed either via ER associated degradation (ERAD), which is proteasome-mediated, or via autophagy. One such substrate is the "Z" variant of the alpha-1 protease inhibitor (A1 Pi), variably known as A1 Pi-Z or ATZ ("anti-trypsin, Z variant"). The wild type protein is primarily synthesized in the liver and is secreted. In contrast, AT-Z, like other ERAD substrates, is retro-translocated from the ER and delivered to the proteasome. However, ATZ can form high molecular weight polymers that are degraded via autophagy, and cells that accumulate ATZ polymers ultimately succumb, which leads to liver disease. Therefore, identifying genes that have an impact ATZ turnover represents an active area of research. To this end, a yeast expression system for ATZ has proven valuable. For example, a recent study using this system indicates that the activity of a proteasome assembly chaperone (PAC) is critical for maximal ATZ turnover, which suggests a new role for PACs. Because PACs are conserved, it will be critical to analyze whether these dedicated chaperones are implicated in other diseases associated with ERAD and autophagy.