Rusten Tor Erik, Vaccari Thomas, Lindmo Karine, Rodahl Lina M W, Nezis Ioannis P, Sem-Jacobsen Catherine, Wendler Franz, Vincent Jean-Paul, Brech Andreas, Bilder David, Stenmark Harald
Centre for Cancer Biomedicine, University of Oslo, N-0310 Oslo, Norway.
Curr Biol. 2007 Oct 23;17(20):1817-25. doi: 10.1016/j.cub.2007.09.032. Epub 2007 Oct 11.
Eukaryotes use autophagy to turn over organelles, protein aggregates, and cytoplasmic constituents. The impairment of autophagy causes developmental defects, starvation sensitivity, the accumulation of protein aggregates, neuronal degradation, and cell death [1, 2]. Double-membraned autophagosomes sequester cytoplasm and fuse with endosomes or lysosomes in higher eukaryotes [3], but the importance of the endocytic pathway for autophagy and associated disease is not known. Here, we show that regulators of endosomal biogenesis and functions play a critical role in autophagy in Drosophila melanogaster. Genetic and ultrastructural analysis showed that subunits of endosomal sorting complex required for transport (ESCRT)-I, -II and -III, as well as their regulatory ATPase Vps4 and the endosomal PtdIns(3)P 5-kinase Fab1, all are required for autophagy. Although the loss of ESCRT or Vps4 function caused the accumulation of autophagosomes, probably because of inhibited fusion with the endolysosomal system, Fab1 activity was necessary for the maturation of autolysosomes. Importantly, reduced ESCRT functions aggravated polyglutamine-induced neurotoxicity in a model for Huntington's disease. Thus, this study links ESCRT function with autophagy and aggregate-induced neurodegeneration, thereby providing a plausible explanation for the fact that ESCRT mutations are involved in inherited neurodegenerative disease in humans [4].
真核生物利用自噬来更新细胞器、蛋白质聚集体和细胞质成分。自噬功能受损会导致发育缺陷、饥饿敏感性、蛋白质聚集体积累、神经元退化和细胞死亡[1,2]。在高等真核生物中，双膜自噬体隔离细胞质并与内体或溶酶体融合[3]，但内吞途径对自噬及相关疾病的重要性尚不清楚。在此，我们表明内体生物发生和功能的调节因子在黑腹果蝇的自噬中起关键作用。遗传和超微结构分析表明，转运所需内体分选复合体（ESCRT）-I、-II和-III的亚基，以及它们的调节性ATP酶Vps4和内体磷脂酰肌醇（3）磷酸5激酶Fab1，都是自噬所必需的。尽管ESCRT或Vps4功能丧失导致自噬体积累，这可能是由于与内溶酶体系统的融合受到抑制，但Fab1活性对于自溶酶体的成熟是必需的。重要的是，在亨廷顿舞蹈病模型中，ESCRT功能降低加剧了多聚谷氨酰胺诱导的神经毒性。因此，本研究将ESCRT功能与自噬及聚集体诱导的神经退行性变联系起来，从而为ESCRT突变与人类遗传性神经退行性疾病有关这一事实提供了一个合理的解释[4]。
