Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB20XY, UK.
J Cell Sci. 2011 Feb 1;124(Pt 3):469-82. doi: 10.1242/jcs.076489.
Autophagy is a lysosome-dependent cellular catabolic mechanism that mediates the turnover of intracellular organelles and long-lived proteins. Reduced autophagic activity has been shown to lead to the accumulation of misfolded proteins in neurons and might be involved in chronic neurodegenerative diseases. Here, we uncover an essential role for the syntaxin-5 SNARE complex in autophagy. Using genetic knockdown, we show that the syntaxin-5 SNARE complex regulates the later stages of autophagy after the initial formation of autophagosomes. This SNARE complex acts on autophagy by regulating ER-to-Golgi transport through the secretory pathway, which is essential for the activity of lysosomal proteases such as cathepsins. Depletion of syntaxin-5 complex components results in the accumulation of autophagosomes as a result of lysosomal dysfunction, leading to decreased degradation of autophagic substrates. Our findings provide a novel link between a fundamental process such as intracellular trafficking and human diseases that might be affected by defective biogenesis and/or homeostasis of the autophagosome-lysosome degradation system.
自噬是一种溶酶体依赖性的细胞分解代谢机制，介导细胞内细胞器和长寿蛋白质的周转。已经表明，自噬活性的降低会导致神经元中错误折叠蛋白质的积累，并且可能与慢性神经退行性疾病有关。在这里，我们揭示了突触融合蛋白 5（syntaxin-5）SNARE 复合物在自噬中的重要作用。通过基因敲低，我们表明突触融合蛋白 5 SNARE 复合物在自噬体形成后的初始阶段之后调节自噬的后期阶段。该 SNARE 复合物通过调节通过分泌途径的内质网到高尔基体的运输来作用于自噬，这对于溶酶体蛋白酶（如组织蛋白酶）的活性至关重要。突触融合蛋白 5 复合物成分的耗竭会导致溶酶体功能障碍，从而导致自噬体的积累，进而导致自噬底物的降解减少。我们的发现提供了一个新的联系，即将细胞内运输等基本过程与可能受到自噬体-溶酶体降解系统的生物发生和/或动态平衡缺陷影响的人类疾病联系起来。
