A gene network regulating lysosomal biogenesis and function.
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.
Sardiello
Marco
M
Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Naples, Italy.
Palmieri
Michela
M
di Ronza
Alberto
A
Medina
Diego Luis
DL
Valenza
Marta
M
Gennarino
Vincenzo Alessandro
VA
Di Malta
Chiara
C
Donaudy
Francesca
F
Embrione
Valerio
V
Polishchuk
Roman S
RS
Banfi
Sandro
S
Parenti
Giancarlo
G
Cattaneo
Elena
E
Ballabio
Andrea
A
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016384:Consensus Sequence; D053263:Gene Regulatory Networks; D006367:HeLa Cells; D006801:Humans; D055029:Inverted Repeat Sequences; D008247:Lysosomes / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D011401:Promoter Regions, Genetic; D013395:Sucrose / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C064972:TFEB protein, human; D014157:Transcription Factors; D013395:Sucrose