Sardiello Marco, Palmieri Michela, di Ronza Alberto, Medina Diego Luis, Valenza Marta, Gennarino Vincenzo Alessandro, Di Malta Chiara, Donaudy Francesca, Embrione Valerio, Polishchuk Roman S, Banfi Sandro, Parenti Giancarlo, Cattaneo Elena, Ballabio Andrea
Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Naples, Italy.
Science. 2009 Jul 24;325(5939):473-7. doi: 10.1126/science.1174447. Epub 2009 Jun 25.
Lysosomes are organelles central to degradation and recycling processes in animal cells. Whether lysosomal activity is coordinated to respond to cellular needs remains unclear. We found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor EB (TFEB). Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induced lysosomal biogenesis and increased the degradation of complex molecules, such as glycosaminoglycans and the pathogenic protein that causes Huntington's disease. Thus, a genetic program controls lysosomal biogenesis and function, providing a potential therapeutic target to enhance cellular clearing in lysosomal storage disorders and neurodegenerative diseases.
溶酶体是动物细胞中降解和循环利用过程的核心细胞器。溶酶体活性是否能协调以响应细胞需求仍不清楚。我们发现，大多数溶酶体基因表现出协调的转录行为，并受转录因子EB（TFEB）调控。在异常的溶酶体储存条件下，TFEB从细胞质转移到细胞核，导致其靶基因激活。在培养细胞中过表达TFEB可诱导溶酶体生物发生，并增加复杂分子（如糖胺聚糖和导致亨廷顿舞蹈病的致病蛋白）的降解。因此，一个遗传程序控制着溶酶体的生物发生和功能，为增强溶酶体储存障碍和神经退行性疾病中的细胞清除提供了一个潜在的治疗靶点。
