• DOI:10.1126/science.1174447
• Corpus ID: 20353685

A Gene Network Regulating Lysosomal Biogenesis and Function

@article{Sardiello2009AGN,
  title={A Gene Network Regulating Lysosomal Biogenesis and Function},
  author={Marco Sardiello and Michela Palmieri and Alberto di Ronza and Diego Luis Medina and Marta Valenza and Vincenzo Alessandro Gennarino and Chiara Di Malta and Francesca Donaudy and Valerio Embrione and Roman S. Polishchuk and Sandro Banfi and Giancarlo Parenti and Elena Cattaneo and Andrea Ballabio},
  journal={Science},
  year={2009},
  volume={325},
  pages={473 - 477}
}

• M. Sardiello, M. Palmieri, +11 authors A. Ballabio
• Published 24 July 2009
• Biology
• Science

Master Controller Cellular organelles allow the localized regulation of specialized processes. Under certain conditions, such as increased growth, organelles may be required to alter their function. Coordinated regulation of the gene networks required for mitochondrial and endoplasmic reticulum function has been observed. Now, Sardiello et al. (p. 473; published online 25 June) have discovered a gene network regulating the lysosome, the major organelle involved in the degradation of internalized macromolecules. Many lysosomal genes were regulated by a single transcription factor, TFEB. TFEB itself can be activated when the lysosome malfunctions and can regulate both the abundance of lysosomes found in the cell, as well as the ability to degrade complex molecules, including a mutant protein that accumulates in patients with Huntington's disease. These results may have implications for the treatment of human lysosomal storage disorders, which are characterized by the aberrant accumulation of macromolecules causing cellular dysfunction. Coordination of the genes that regulate lysosomal biogenesis occurs via a shared sequence motif and one transcription factor. 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.