Autophagy Laboratory, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tübingen, Germany.
J Cell Mol Med. 2011 Sep;15(9):2007-10. doi: 10.1111/j.1582-4934.2011.01339.x.
Autophagy defines the lifespan of eukaryotic organisms by ensuring cellular survival through regulated bulk clearance of proteins, organelles and membranes. Pathophysiological consequences of improper autophagy give rise to a variety of age-related human diseases such as cancer and neurodegeneration. Rational therapeutic implementation of autophagy modulation remains problematic, as fundamental molecular details such as the generation of autophagosomes, unique double-membrane vesicles formed to permit the process of autophagy, are insufficiently understood. Here, freeze-fracture replica immunolabelling reveals WD-repeat protein interacting with phosphoinositides 1 and 2 (WIPI-1 and WIPI-2) as membrane components of autophagosomes and the plasma membrane (PM). In addition, WIPI-1 is also present in membranes of the endoplasmic reticulum (ER) and WIPI-2 was further detected in membranes close to the Golgi cisternae. Our results identify WIPI-1 and WIPI-2 as novel protein components of autophagosomes, and of membrane sites from which autophagosomes might originate (ER, PM, Golgi area). Hence therapeutic modulation of autophagy could involve approaches that functionally target human WIPI proteins.
自噬通过有规律地批量清除蛋白质、细胞器和膜来确保细胞存活，从而定义了真核生物的寿命。自噬不当的病理生理后果会导致各种与年龄相关的人类疾病，如癌症和神经退行性疾病。自噬调节的合理治疗实施仍然存在问题，因为基本的分子细节，如自噬体的产生，即形成允许自噬过程的独特双层膜囊泡，还没有得到充分的理解。在这里，冷冻断裂复型免疫标记显示 WD 重复蛋白与磷酸肌醇 1 和 2（WIPI-1 和 WIPI-2）相互作用，是自噬体和质膜（PM）的膜成分。此外，WIPI-1 也存在于内质网（ER）的膜中，WIPI-2 进一步被检测到在靠近高尔基潴腔的膜中。我们的结果表明，WIPI-1 和 WIPI-2 是自噬体的新型蛋白质成分，也是自噬体可能起源的膜部位（ER、PM、高尔基区）。因此，自噬的治疗调节可能涉及针对人类 WIPI 蛋白的功能靶向方法。
