Kruse Kristina B, Brodsky Jeffrey L, McCracken Ardythe A
Biology Department, University of Nevada, Reno, Nevada 89557, USA.
Autophagy. 2006 Apr-Jun;2(2):135-7. doi: 10.4161/auto.2.2.2388. Epub 2006 Apr 6.
Protein quality control processes active in the endoplasmic reticulum (ER), including ER-associated protein degradation (ERAD) and the unfolded protein response (UPR), prevent the cytotoxic effects that can result from the accumulation of misfolded proteins. Characterization of a yeast mutant deficient in ERAD, a proteasome-dependent degradation pathway, revealed the employment of two overflow pathways from the ER to the vacuole when ERAD was compromised. One removes the soluble misfolded protein via the biosynthetic pathway and the second clears aggregated proteins via autophagy. Previously, autophagy had been implicated in the clearance of cytoplasmic aggresomes, but was not known to play a direct role in ER protein quality control. These findings provide insight into the molecular mechanisms that result in the gain-of-function liver disease associated with both alpha1-deficiency and hypofibrinogenemia (abnormally low levels of plasma fibrinogen, which is required for blood clotting), and emphasize the need for a more complete understanding of the molecular mechanisms of autophagy and its relationship to protein quality control.
在内质网（ER）中活跃的蛋白质质量控制过程，包括内质网相关蛋白降解（ERAD）和未折叠蛋白反应（UPR），可防止因错误折叠蛋白积累而产生的细胞毒性作用。对一种缺乏ERAD（一种蛋白酶体依赖性降解途径）的酵母突变体的表征揭示，当ERAD受损时，会采用两条从内质网到液泡的溢流途径。一条通过生物合成途径清除可溶性错误折叠蛋白，另一条通过自噬清除聚集蛋白。此前，自噬被认为与细胞质聚集体的清除有关，但尚不清楚它在内质网蛋白质质量控制中是否发挥直接作用。这些发现为导致与α1缺乏症和低纤维蛋白原血症（血浆纤维蛋白原水平异常低，而血浆纤维蛋白原是血液凝固所必需的）相关的功能获得性肝病的分子机制提供了见解，并强调需要更全面地了解自噬的分子机制及其与蛋白质质量控制的关系。
