Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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}tigem.it

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS).
T. Bachetti, S. Chiesa, P. Castagnola, D. Bani, E. Di Zanni, A. Omenetti, A. D'Osualdo, A. Fraldi, A. Ballabio, R. Ravazzolo, et al. (2013)
Ann Rheum Dis 72, 1044-1052
   Abstract »    Full Text »    PDF »
TFEB regulates lysosomal proteostasis.
W. Song, F. Wang, M. Savini, A. Ake, A. di Ronza, M. Sardiello, and L. Segatori (2013)
Hum. Mol. Genet. 22, 1994-2009
   Abstract »    Full Text »    PDF »
TFEB-mediated autophagy rescues midbrain dopamine neurons from {alpha}-synuclein toxicity.
M. Decressac, B. Mattsson, P. Weikop, M. Lundblad, J. Jakobsson, and A. Bjorklund (2013)
PNAS 110, E1817-E1826
   Abstract »    Full Text »    PDF »
A RANKL-PKC{beta}-TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts.
M. Ferron, C. Settembre, J. Shimazu, J. Lacombe, S. Kato, D. J. Rawlings, A. Ballabio, and G. Karsenty (2013)
Genes & Dev. 27, 955-969
   Abstract »    Full Text »    PDF »
Chaperone-mediated Autophagy Targets Hypoxia-inducible Factor-1{alpha} (HIF-1{alpha}) for Lysosomal Degradation.
M. E. Hubbi, H. Hu, Kshitiz, I. Ahmed, A. Levchenko, and G. L. Semenza (2013)
J. Biol. Chem. 288, 10703-10714
   Abstract »    Full Text »    PDF »
hLGDB: a database of human lysosomal genes and their regulation.
A. Brozzi, L. Urbanelli, P. Luc Germain, A. Magini, and C. Emiliani (2013)
Database 2013, bat024
   Abstract »    Full Text »    PDF »
Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes.
J. A. Martina and R. Puertollano (2013)
J. Cell Biol. 200, 475-491
   Abstract »    Full Text »    PDF »
The cell biology of disease: Lysosomal storage disorders: The cellular impact of lysosomal dysfunction.
F. M. Platt, B. Boland, and A. C. van der Spoel (2012)
J. Cell Biol. 199, 723-734
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-{beta} Precursor Protein.
C. Parr, R. Carzaniga, S. M. Gentleman, F. Van Leuven, J. Walter, and M. Sastre (2012)
Mol. Cell. Biol. 32, 4410-4418
   Abstract »    Full Text »    PDF »
Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6.
T. Unno, M. Wakamori, M. Koike, Y. Uchiyama, K. Ishikawa, H. Kubota, T. Yoshida, H. Sasakawa, C. Peters, H. Mizusawa, et al. (2012)
PNAS 109, 17693-17698
   Abstract »    Full Text »    PDF »
Expression Profiling and Biochemical Analysis Suggest Stress Response as a Potential Mechanism Inhibiting Proliferation of Polyamine-depleted Cells.
G. Landau, A. Ran, Z. Bercovich, E. Feldmesser, S. Horn-Saban, E. Korkotian, J. Jacob-Hirsh, G. Rechavi, D. Ron, and C. Kahana (2012)
J. Biol. Chem. 287, 35825-35837
   Abstract »    Full Text »    PDF »
PGC-1{alpha} Rescues Huntington's Disease Proteotoxicity by Preventing Oxidative Stress and Promoting TFEB Function.
T. Tsunemi, T. D. Ashe, B. E. Morrison, K. R. Soriano, J. Au, R. A. V. Roque, E. R. Lazarowski, V. A. Damian, E. Masliah, and A. R. La Spada (2012)
Science Translational Medicine 4, 142ra97
   Abstract »    Full Text »    PDF »
Presenilins: A novel link between intracellular calcium signaling and lysosomal function?.
I. Bezprozvanny (2012)
J. Cell Biol. 198, 7-10
   Abstract »    Full Text »    PDF »
Immune regulation of Rab proteins expression and intracellular transport.
G. Pei, M. Bronietzki, and M. G. Gutierrez (2012)
J. Leukoc. Biol. 92, 41-50
   Abstract »    Full Text »    PDF »
State of the Science: An Update on Renal Cell Carcinoma.
E. Jonasch, P. A. Futreal, I. J. Davis, S. T. Bailey, W. Y. Kim, J. Brugarolas, A. J. Giaccia, G. Kurban, A. Pause, J. Frydman, et al. (2012)
Mol. Cancer Res. 10, 859-880
   Abstract »    Full Text »    PDF »
A Role for Presenilins in Autophagy Revisited: Normal Acidification of Lysosomes in Cells Lacking PSEN1 and PSEN2.
X. Zhang, K. Garbett, K. Veeraraghavalu, B. Wilburn, R. Gilmore, K. Mirnics, and S. S. Sisodia (2012)
J. Neurosci. 32, 8633-8648
   Abstract »    Full Text »    PDF »
The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis.
A. Roczniak-Ferguson, C. S. Petit, F. Froehlich, S. Qian, J. Ky, B. Angarola, T. C. Walther, and S. M. Ferguson (2012)
Science Signaling 5, ra42
   Abstract »    Full Text »    PDF »
Identification of microRNA-regulated gene networks by expression analysis of target genes.
V. A. Gennarino, G. D'Angelo, G. Dharmalingam, S. Fernandez, G. Russolillo, R. Sanges, M. Mutarelli, V. Belcastro, A. Ballabio, P. Verde, et al. (2012)
Genome Res. 22, 1163-1172
   Abstract »    Full Text »    PDF »
Cathepsins L and Z Are Critical in Degrading Polyglutamine-containing Proteins within Lysosomes.
N. Bhutani, R. Piccirillo, R. Hourez, P. Venkatraman, and A. L. Goldberg (2012)
J. Biol. Chem. 287, 17471-17482
   Abstract »    Full Text »    PDF »
Loss of Lysosomal Ion Channel Transient Receptor Potential Channel Mucolipin-1 (TRPML1) Leads to Cathepsin B-dependent Apoptosis.
G. A. Colletti, M. T. Miedel, J. Quinn, N. Andharia, O. A. Weisz, and K. Kiselyov (2012)
J. Biol. Chem. 287, 8082-8091
   Abstract »    Full Text »    PDF »
Excessive activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II.
A. C. Petrey, H. Flanagan-Steet, S. Johnson, X. Fan, M. De la Rosa, M. E. Haskins, A. V. Nairn, K. W. Moremen, and R. Steet (2012)
Dis. Model. Mech. 5, 177-190
   Abstract »    Full Text »    PDF »
Autophagy Driven by a Master Regulator of Hematopoiesis.
Y.-A. Kang, R. Sanalkumar, H. O'Geen, A. K. Linnemann, C.-J. Chang, E. E. Bouhassira, P. J. Farnham, S. Keles, and E. H. Bresnick (2012)
Mol. Cell. Biol. 32, 226-239
   Abstract »    Full Text »    PDF »
Endocytosis and Signaling: Cell Logistics Shape the Eukaryotic Cell Plan.
S. Sigismund, S. Confalonieri, A. Ciliberto, S. Polo, G. Scita, and P. P. Di Fiore (2012)
Physiol Rev 92, 273-366
   Abstract »    Full Text »    PDF »
Transcriptional gene network inference from a massive dataset elucidates transcriptome organization and gene function.
V. Belcastro, V. Siciliano, F. Gregoretti, P. Mithbaokar, G. Dharmalingam, S. Berlingieri, F. Iorio, G. Oliva, R. Polishchuck, N. Brunetti-Pierri, et al. (2011)
Nucleic Acids Res. 39, 8677-8688
   Abstract »    Full Text »    PDF »
Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts.
T. Otomo, K. Higaki, E. Nanba, K. Ozono, and N. Sakai (2011)
J. Biol. Chem. 286, 35283-35290
   Abstract »    Full Text »    PDF »
Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways.
M. Palmieri, S. Impey, H. Kang, A. di Ronza, C. Pelz, M. Sardiello, and A. Ballabio (2011)
Hum. Mol. Genet. 20, 3852-3866
   Abstract »    Full Text »    PDF »
Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells.
T. Lemonnier, S. Blanchard, D. Toli, E. Roy, S. Bigou, R. Froissart, I. Rouvet, S. Vitry, J. M. Heard, and D. Bohl (2011)
Hum. Mol. Genet. 20, 3653-3666
   Abstract »    Full Text »    PDF »
Biology and Clinical Relevance of the Micropthalmia Family of Transcription Factors in Human Cancer.
R. Haq and D. E. Fisher (2011)
J. Clin. Oncol. 29, 3474-3482
   Abstract »    Full Text »    PDF »
SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization.
A. K. Stewart, B. E. Shmukler, D. H. Vandorpe, F. Reimold, J. F. Heneghan, M. Nakakuki, A. Akhavein, S. Ko, H. Ishiguro, and S. L. Alper (2011)
Am J Physiol Cell Physiol 301, C289-C303
   Abstract »    Full Text »    PDF »
Identification of a Lysosomal Pathway That Modulates Glucocorticoid Signaling and the Inflammatory Response.
Y. He, Y. Xu, C. Zhang, X. Gao, K. J. Dykema, K. R. Martin, J. Ke, E. A. Hudson, S. K. Khoo, J. H. Resau, et al. (2011)
Science Signaling 4, ra44
   Abstract »    Full Text »    PDF »
g:Profiler--a web server for functional interpretation of gene lists (2011 update).
J. Reimand, T. Arak, and J. Vilo (2011)
Nucleic Acids Res. 39, W307-W315
   Abstract »    Full Text »    PDF »
Autophagy's Top Chef.
A. M. Cuervo (2011)
Science 332, 1392-1393
   Abstract »    Full Text »    PDF »
TFEB Links Autophagy to Lysosomal Biogenesis.
C. Settembre, C. Di Malta, V. A. Polito, M. G. Arencibia, F. Vetrini, S. Erdin, S. U. Erdin, T. Huynh, D. Medina, P. Colella, et al. (2011)
Science 332, 1429-1433
   Abstract »    Full Text »    PDF »
Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes.
M. Boonen, E. van Meel, V. Oorschot, J. Klumperman, and S. Kornfeld (2011)
Mol. Biol. Cell 22, 1135-1147
   Abstract »    Full Text »    PDF »
Reverse Engineering Gene Network Identifies New Dysferlin-interacting Proteins.
M. Cacciottolo, V. Belcastro, S. Laval, K. Bushby, D. di Bernardo, and V. Nigro (2011)
J. Biol. Chem. 286, 5404-5413
   Abstract »    Full Text »    PDF »
Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase.
A. Capell, S. Liebscher, K. Fellerer, N. Brouwers, M. Willem, S. Lammich, I. Gijselinck, T. Bittner, A. M. Carlson, F. Sasse, et al. (2011)
J. Neurosci. 31, 1885-1894
   Abstract »    Full Text »    PDF »
Transcription factor MIST1 in terminal differentiation of mouse and human plasma cells.
B. J. Capoccia, J. K. M. Lennerz, A. J. Bredemeyer, J. M. Klco, J. L. Frater, and J. C. Mills (2011)
Physiol Genomics 43, 174-186
   Abstract »    Full Text »    PDF »
Pathogenic Lysosomal Depletion in Parkinson's Disease.
B. Dehay, J. Bove, N. Rodriguez-Muela, C. Perier, A. Recasens, P. Boya, and M. Vila (2010)
J. Neurosci. 30, 12535-12544
   Abstract »    Full Text »    PDF »
Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease.
C. Zuccato, M. Valenza, and E. Cattaneo (2010)
Physiol Rev 90, 905-981
   Abstract »    Full Text »    PDF »
Drosophila acinus encodes a novel regulator of endocytic and autophagic trafficking.
A. S. Haberman, M. A. Akbar, S. Ray, and H. Kramer (2010)
Development 137, 2157-2166
   Abstract »    Full Text »    PDF »
Cdx2 regulates endo-lysosomal function and epithelial cell polarity.
N. Gao and K. H. Kaestner (2010)
Genes & Dev. 24, 1295-1305
   Abstract »    Full Text »    PDF »
RAB26 and RAB3D Are Direct Transcriptional Targets of MIST1 That Regulate Exocrine Granule Maturation.
X. Tian, R. U. Jin, A. J. Bredemeyer, E. J. Oates, K. M. Blazewska, C. E. McKenna, and J. C. Mills (2010)
Mol. Cell. Biol. 30, 1269-1284
   Abstract »    Full Text »    PDF »
Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response.
S. Schuck, W. A. Prinz, K. S. Thorn, C. Voss, and P. Walter (2009)
J. Cell Biol. 187, 525-536
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882