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.


Logo for

Science 332 (6036): 1429-1433

Copyright © 2011 by the American Association for the Advancement of Science

TFEB Links Autophagy to Lysosomal Biogenesis

Carmine Settembre,1,2,3 Chiara Di Malta,1 Vinicia Assunta Polito,1,2,3 Moises Garcia Arencibia,4 Francesco Vetrini,2 Serkan Erdin,2,3 Serpil Uckac Erdin,2,3 Tuong Huynh,2,3 Diego Medina,1 Pasqualina Colella,1 Marco Sardiello,2,3 David C. Rubinsztein,4 Andrea Ballabio1,2,3,5,*

Abstract: Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal–regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase–dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.

1 Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, 80131 Naples, Italy.
2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3 Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA.
4 Cambridge Institute for Medical Research, Wellcome Trust–Medical Research Council Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0XY, UK.
5 Medical Genetics, Department of Pediatrics, Federico II University, Via Pansini 5, 80131 Naples, Italy.

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

The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function.
Y. Qin, Y. Deng, C. J. Ricketts, S. Srikantan, E. Wang, E. R. Maher, and P. L. M. Dahia (2014)
Hum. Mol. Genet. 23, 2428-2439
   Abstract »    Full Text »    PDF »
2-Hydroxypropyl-{beta}-cyclodextrin Promotes Transcription Factor EB-mediated Activation of Autophagy: IMPLICATIONS FOR THERAPY.
W. Song, F. Wang, P. Lotfi, M. Sardiello, and L. Segatori (2014)
J. Biol. Chem. 289, 10211-10222
   Abstract »    Full Text »    PDF »
Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1.
A. Di Nardo, M. H. Wertz, E. Kwiatkowski, P. T. Tsai, J. D. Leech, E. Greene-Colozzi, J. Goto, P. Dilsiz, D. M. Talos, C. B. Clish, et al. (2014)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »
Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy.
J. P. Chua, S. L. Reddy, D. E. Merry, H. Adachi, M. Katsuno, G. Sobue, D. M. Robins, and A. P. Lieberman (2014)
Hum. Mol. Genet. 23, 1376-1386
   Abstract »    Full Text »    PDF »
Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy.
G. Tohnai, H. Adachi, M. Katsuno, H. Doi, S. Matsumoto, N. Kondo, Y. Miyazaki, M. Iida, H. Nakatsuji, Q. Qiang, et al. (2014)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »
GCN5-like Protein 1 (GCN5L1) Controls Mitochondrial Content through Coordinated Regulation of Mitochondrial Biogenesis and Mitophagy.
I. Scott, B. R. Webster, C. K. Chan, J. U. Okonkwo, K. Han, and M. N. Sack (2014)
J. Biol. Chem. 289, 2864-2872
   Abstract »    Full Text »    PDF »
Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease.
S. Sciarretta, M. Volpe, and J. Sadoshima (2014)
Circ. Res. 114, 549-564
   Abstract »    Full Text »    PDF »
The Nutrient-Responsive Transcription Factor TFE3 Promotes Autophagy, Lysosomal Biogenesis, and Clearance of Cellular Debris.
J. A. Martina, H. I. Diab, L. Lishu, L. Jeong-A, S. Patange, N. Raben, and R. Puertollano (2014)
Science Signaling 7, ra9
   Abstract »    Full Text »    PDF »
The Innate Immune Factor Apolipoprotein L1 Restricts HIV-1 Infection.
H. E. Taylor, A. K. Khatua, and W. Popik (2014)
J. Virol. 88, 592-603
   Abstract »    Full Text »    PDF »
Suppression of Lysosome Function Induces Autophagy via a Feedback Down-regulation of MTOR Complex 1 (MTORC1) Activity.
M. Li, B. Khambu, H. Zhang, J.-H. Kang, X. Chen, D. Chen, L. Vollmer, P.-Q. Liu, A. Vogt, and X.-M. Yin (2013)
J. Biol. Chem. 288, 35769-35780
   Abstract »    Full Text »    PDF »
Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies.
M. Sandri, L. Coletto, P. Grumati, and P. Bonaldo (2013)
J. Cell Sci. 126, 5325-5333
   Abstract »    Full Text »    PDF »
Epigenetic Regulation of Autophagy by the Methyltransferase G9a.
A. Artal-Martinez de Narvajas, T. S. Gomez, J.-S. Zhang, A. O. Mann, Y. Taoda, J. A. Gorman, M. Herreros-Villanueva, T. M. Gress, V. Ellenrieder, L. Bujanda, et al. (2013)
Mol. Cell. Biol. 33, 3983-3993
   Abstract »    Full Text »    PDF »
Autophagy in blood cancers: biological role and therapeutic implications.
A. Nencioni, M. Cea, F. Montecucco, V. D. Longo, F. Patrone, A. M. Carella, T. L. Holyoake, and G. V. Helgason (2013)
Haematologica 98, 1335-1343
   Abstract »    Full Text »    PDF »
The lysosome: from waste bag to potential therapeutic target.
H. Appelqvist, P. Waster, K. Kagedal, and K. Ollinger (2013)
J Mol Cell Biol 5, 214-226
   Abstract »    Full Text »    PDF »
Differential Contribution of Insulin and Amino Acids to the mTORC1-Autophagy Pathway in the Liver and Muscle.
T. Naito, A. Kuma, and N. Mizushima (2013)
J. Biol. Chem. 288, 21074-21081
   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 »
Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease.
C. Spampanato, E. Feeney, L. Li, M. Cardone, J.-A. Lim, F. Annunziata, H. Zare, R. Polishchuk, R. Puertollano, G. Parenti, et al. (2013)
EMBO Mol Med. 5, 691-706
   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 »
Regulation of mTORC1 and its impact on gene expression at a glance.
M. Laplante and D. M. Sabatini (2013)
J. Cell Sci. 126, 1713-1719
   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 »
Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency.
N. Pastore, K. Blomenkamp, F. Annunziata, P. Piccolo, P. Mithbaokar, R. Maria Sepe, F. Vetrini, D. Palmer, P. Ng, E. Polishchuk, et al. (2013)
EMBO Mol Med. 5, 397-412
   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 »
PIPing on lysosome tubes.
N. T. Ktistakis and S. A. Tooze (2013)
EMBO J. 32, 315-317
   Full Text »    PDF »
Defective Autophagy and mTORC1 Signaling in Myotubularin Null Mice.
K. M. Fetalvero, Y. Yu, M. Goetschkes, G. Liang, R. A. Valdez, T. Gould, E. Triantafellow, S. Bergling, J. Loureiro, J. Eash, et al. (2013)
Mol. Cell. Biol. 33, 98-110
   Abstract »    Full Text »    PDF »
Functional classification of skeletal muscle networks. II. Applications to pathophysiology.
Y. Wang, J. Winters, and S. Subramaniam (2012)
J Appl Physiol 113, 1902-1920
   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 »
MicroRNA regulation of autophagy.
L. B. Frankel and A. H. Lund (2012)
Carcinogenesis 33, 2018-2025
   Abstract »    Full Text »    PDF »
Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition.
M. Cea, A. Cagnetta, M. Fulciniti, Y.-T. Tai, T. Hideshima, D. Chauhan, A. Roccaro, A. Sacco, T. Calimeri, F. Cottini, et al. (2012)
Blood 120, 3519-3529
   Abstract »    Full Text »    PDF »
Autophagy and Neuronal Cell Death in Neurological Disorders.
R. A. Nixon and D.-S. Yang (2012)
Cold Spring Harb Perspect Biol 4, a008839
   Abstract »    Full Text »    PDF »
Plenary Perspective: The complexity of constitutive and inducible gene expression in mononuclear phagocytes.
D. A. Hume (2012)
J. Leukoc. Biol. 92, 433-444
   Abstract »    Full Text »    PDF »
Hepatitis C Virus Upregulates Beclin1 for Induction of Autophagy and Activates mTOR Signaling.
S. Shrivastava, J. Bhanja Chowdhury, R. Steele, R. Ray, and R. B. Ray (2012)
J. Virol. 86, 8705-8712
   Abstract »    Full Text »    PDF »
The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease.
Y. Ihara, M. Morishima-Kawashima, and R. Nixon (2012)
Cold Spring Harb Perspect Med 2, a006361
   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 »
Autophagy: An Emerging Immunological Paradigm.
V. Deretic (2012)
J. Immunol. 189, 15-20
   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 »
Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy.
R. L. Vidal, A. Figueroa, F. A. Court, P. Thielen, C. Molina, C. Wirth, B. Caballero, R. Kiffin, J. Segura-Aguilar, A. M. Cuervo, et al. (2012)
Hum. Mol. Genet. 21, 2245-2262
   Abstract »    Full Text »    PDF »
Autophagy and cell growth - the yin and yang of nutrient responses.
T. P. Neufeld (2012)
J. Cell Sci. 125, 2359-2368
   Abstract »    Full Text »    PDF »
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.
C. Settembre, R. Zoncu, D. L. Medina, F. Vetrini, S. Erdin, S. Erdin, T. Huynh, M. Ferron, G. Karsenty, M. C. Vellard, et al. (2012)
EMBO J. 31, 1095-1108
   Abstract »    Full Text »    PDF »
FRS2{alpha}-Mediated FGF Signals Suppress Premature Differentiation of Cardiac Stem Cells Through Regulating Autophagy Activity.
J. Zhang, J. Liu, Y. Huang, J. Y. F. Chang, L. Liu, W. L. McKeehan, J. F. Martin, and F. Wang (2012)
Circ. Res. 110, e29-e39
   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 »
Autophagy regulation by miRNAs: when cleaning goes out of service.
F. Cecconi (2011)
EMBO J. 30, 4517-4519
   Abstract »    Full Text »    PDF »
Temporal orchestration of circadian autophagy rhythm by C/EBP{beta}.
D. Ma, S. Panda, and J. D. Lin (2011)
EMBO J. 30, 4642-4651
   Abstract »    Full Text »    PDF »
BAX inhibitor-1 regulates autophagy by controlling the IRE1{alpha} branch of the unfolded protein response.
K. Castillo, D. Rojas-Rivera, F. Lisbona, B. Caballero, M. Nassif, F. A. Court, S. Schuck, C. Ibar, P. Walter, J. Sierralta, et al. (2011)
EMBO J. 30, 4465-4478
   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 »
TFEBulous control of traffic by mTOR.
E. Jacinto (2011)
EMBO J. 30, 3215-3216
   Abstract »    Full Text »    PDF »
Regulation of TFEB and V-ATPases by mTORC1.
S. Pena-Llopis, S. Vega-Rubin-de-Celis, J. C. Schwartz, N. C. Wolff, T. A. T. Tran, L. Zou, X.-J. Xie, D. R. Corey, and J. Brugarolas (2011)
EMBO J. 30, 3242-3258
   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 »
Autophagy's Top Chef.
A. M. Cuervo (2011)
Science 332, 1392-1393
   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