A Gene Network Regulating Lysosomal Biogenesis and Function

Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Naples, Italy.
Science (Impact Factor: 31.48). 07/2009; 325(5939):473-7. DOI: 10.1126/science.1174447
Source: PubMed

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.

Download full-text


Available from: Michela Palmieri, Aug 22, 2015
    • "melanoma cell line that stably expresses HA – MITF at comparable levels to the endogenous gene ( supplementary material Fig . S4A ) . Manual inspection of our ChlP - Seq data revealed MITF bound to many lysosomal genes with or without previously identified CLEAR elements ( supplementary material Fig . S4B , C ; supplementary material Table S6A ) ( Sardiello et al . , 2009 ) . More importantly , MITF - binding peaks were also found at a majority of ATP6 loci ( 20 of 25 ; P=0 . 002 ) ( Fig . 6C - C′ ; supplementary material Table S6B ) , confirming and extending previous findings by Strub et al . ( 2011 ) . Strikingly , 19 of the v - ATP6 genes bound by MITF showed positive correlation in the melanoma line"
    [Show abstract] [Hide abstract]
    ABSTRACT: The v-ATPase is a fundamental eukaryotic enzyme central to cellular homeostasis. Although its impact on key metabolic regulators such as TORC1 is well-documented, our knowledge of mechanisms that regulate v-ATPase activity is limited. Here, we report that the Drosophila transcription factor Mitf is a master regulator of this holoenzyme. Mitf directly controls transcription of all 15 v-ATPase components through M-box cis-sites and this coordinated regulation impacts holoenzyme activity in vivo. In addition, through the v-ATPase, Mitf promotes the activity of TORC1, which in turn negatively regulates Mitf. We provide evidence that Mitf, v-ATPase and TORC1 form a negative regulatory loop that maintains each of these important metabolic regulators in relative balance. Interestingly, direct regulation of v-ATPase genes by human MITF also occurs in cells of the melanocytic lineage, showing mechanistic conservation in the regulation of the v-ATPase by MITF-TFE proteins in fly and mammals. Collectively, this evidence points to an ancient Mitf/v-ATPase/TORC1 module that serves as a dynamic modulator of metabolism for cellular homeostasis. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 06/2015; DOI:10.1242/jcs.173807 · 5.33 Impact Factor
  • Source
    • "The recycling of these key metabolic building blocks protects cells from their fatal depletion and thus maintains cellular homeostasis to survive nutrient limitation (Onodera and Ohsumi, 2005; Vabulas and Hartl, 2005; Jones et al., 2012; Suraweera et al., 2012). Therefore evolutionary conserved starvation programs in mammalian cells and yeast expand and strengthen this intracellular recycling system by enhancing the de novo synthesis of vacuolar/lysosomal hydrolases (Gasch et al., 2000; Sardiello et al., 2009; Settembre et al., 2011; Shen and Mizushima, 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The degradation and recycling of cellular components is essential for cell growth and survival. Here we show how selective and non-selective lysosomal protein degradation pathways cooperate to ensure cell survival upon nutrient limitation. A quantitative analysis of starvation-induced proteome remodeling in yeast reveals comprehensive changes already in the first three hours. In this period, many different integral plasma membrane proteins undergo endocytosis and degradation in vacuoles via the multivesicular body (MVB) pathway. Their degradation becomes essential to maintain critical amino acids levels that uphold protein synthesis early during starvation. This promotes cellular adaptation, including the de novo synthesis of vacuolar hydrolases to boost the vacuolar catabolic activity. This order of events primes vacuoles for the efficient degradation of bulk cytoplasm via autophagy. Hence, a catabolic cascade including the coordinated action of the MVB pathway and autophagy is essential to enter quiescence to survive extended periods of nutrient limitation.
    eLife Sciences 04/2015; 4. DOI:10.7554/eLife.07736 · 8.52 Impact Factor
  • Source
    • "The transcription factor EB (TFEB) protein, a member of the basic helix-loop-helix leucine zipper family of transcription factors shown to control expression of many lysosomal genes, is considered a " master regulator " of lysosomal biogenesis [44]. Upon activation, TFEB directly binds to a 10-base pair DNA motif (GTCACGTGAC), known as the Coordinated Lysosomal Expression and Regulation (CLEAR) element, in the promoter regions of many lysosomal and autophagosomal genes, thereby promoting their transcription [44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the last few years extensive studies have linked the activity of mTORC1 to lysosomal function. These observations propose an intriguing integration of cellular catabolism, sustained by lysosomes, with anabolic processes, largely controlled by mTORC1. Interestingly, lysosomal function directly affects mTORC1 activity and is regulated by ZKSCAN3 and TFEB, two transcription factors and substrates of mTORC1. Thus, the lysosomal mTOR signaling complex represents a hub of cellular energy metabolism, and its dysregulation may lead to a number of human diseases. Here, we discuss the recent developments and highlight the open questions in this growing field.
    Journal of Cell Death 01/2015; 1(1). DOI:10.1515/cdth-2015-0001
Show more