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Science 325 (5939): 473-477

Copyright © 2009 by the American Association for the Advancement of Science

A Gene Network Regulating Lysosomal Biogenesis and Function

Marco Sardiello,1 Michela Palmieri,1 Alberto di Ronza,1 Diego Luis Medina,1 Marta Valenza,2 Vincenzo Alessandro Gennarino,1 Chiara Di Malta,1 Francesca Donaudy,1 Valerio Embrione,1 Roman S. Polishchuk,3 Sandro Banfi,1 Giancarlo Parenti,1,4 Elena Cattaneo,2 Andrea Ballabio1,4,*

Abstract: 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.

1 Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Naples, Italy.
2 Department of Pharmacological Sciences and Center for Stem Cell Research, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
3 Telethon Electron Microscopy Core Facility, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, I-66030 Santa Maria Imbaro, Chieti, Italy.
4 Department of Pediatrics, Federico II University, Via S. Pansini 5, 80131 Naples, Italy.

* To whom correspondence should be addressed. E-mail: ballabio{at}

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