Department of Molecular and Cellular Biology, Life Sciences South Room 531, University of Arizona, Tucson, AZ 85721, USA.
Traffic. 2011 Oct;12(10):1417-31. doi: 10.1111/j.1600-0854.2011.01243.x. Epub 2011 Jul 27.
Cells have to maintain stable plasma membrane protein and lipid compositions under normal conditions and to remodel their plasma membranes in response to stimuli. This maintenance and remodeling require that integral membrane proteins at the plasma membrane that become misfolded, because of the relatively harsher extracellular milieu or carbohydrate and amino acid sequence changes, are degraded. We had previously shown that Derlin proteins, required for quality control mechanisms in the endoplasmic reticulum, also localize to endosomes and function in the degradation of misfolded integral membrane proteins at the plasma membrane. In this study, we show that Derlin proteins physically associate with sorting nexins that function in retrograde membrane transport from endosomes to the Golgi apparatus. Using genetic studies in Caenorhabditis elegans and ricin pulse-chase analyses in murine RAW264.7 macrophages, we show that the Derlin-sorting nexin interaction is physiologically relevant. Our studies suggest that at least some integral membrane proteins that are misfolded at the plasma membrane are retrogradely transported to the Golgi apparatus and ultimately to the endoplasmic reticulum for degradation via resident quality control mechanisms.
细胞必须在正常条件下维持稳定的质膜蛋白和脂质组成，并在受到刺激时重塑其质膜。这种维持和重塑需要质膜上的整合膜蛋白发生错误折叠，因为细胞外环境相对恶劣，或者碳水化合物和氨基酸序列发生变化，从而导致这些蛋白降解。我们之前曾表明，内质网质量控制机制所需的 Derlin 蛋白也定位于内体，并在质膜上错误折叠的整合膜蛋白的降解中发挥作用。在这项研究中，我们表明 Derlin 蛋白与参与从内体到高尔基体逆行膜运输的分选连接蛋白物理结合。我们使用秀丽隐杆线虫的遗传研究和鼠源 RAW264.7 巨噬细胞中的蓖麻毒素脉冲追踪分析表明，Derlin-分选连接蛋白相互作用具有生理学相关性。我们的研究表明，至少一些在质膜上错误折叠的整合膜蛋白通过驻留的质量控制机制被逆行运输到高尔基体，并最终运输到内质网进行降解。
