The goal of this project is to gain a deeper knowledge on the mechanisms that regulate the lysosome in an effort to identify novel tools to regulate its function. This knowledge could have a direct impact on the development of therapeutic options for lysosomal storage diseases (LSDs), a group of over 50 inherited diseases with a progressive and multisystemic phenotype, which mostly affect children. In 2009 we discovered that lysosomal function and autophagy are subject to a global transcriptional regulation, which is mediated by the master gene TFEB (Sardiello et al. Science 2009; Settembre et al. Science, 2011). This regulatory pathway allows the lysosome to respond to environmental cues such as starvation, physical exercise, infection, and a variety of stress conditions. TFEB mediates a lysosome-to-nucleus signaling mechanism that originates from the lysosomal surface and is regulated by the mTORC1 kinase. Induction lysosomal biogenesis and autophagy via TFEB has proven to be a potent tool to promote cellular clearance in LSDs and neurodegenerative diseases (Medina et al, Dev Cell,2011, Decressac et al, PNAS, 2013). In spite of these exciting developments several knowledge gaps remain in our understanding of how TFEB is regulated at both transcriptional and post-translational levels and on how we could be modulate lysosomal function and cellular clearance to treat human diseases. This project aims at tackling these gaps by: 1) dissecting the molecular and developmental cues responsible for TFEB transcriptional regulation and on the definition of TFEB epigenetic landscape in steady-state conditions; 2) identifying the pathways that mediate TFEB nuclear export and the players involved. A deeper understanding of these pathways may lead to the identification of tools (and potential targets) to either inhibit or enhance TFEB nuclear export and 3) studying pathways alternative to TFEB that regulate lysosomal function in an effort to identify novel signalling pathways and molecules that regulate, either directly or indirectly, lysosomal function. The results of these studies will be instrumental in identifying new strategies and tools to safely and effectively modulate clearance of lysosomal storage in a variety of diseases.
Lysosomal storage diseases (LSDs) are a group of approximately 50 inherited disorders characterized by progressive symptoms affecting multiple organs due to a defective function of the lysosome, the cellular organelle that is dedicated to the degradation and recycling of the products of cellular metabolism. We demonstrated that lysosomal function is controlled by a gene named TFEB that when activated, promotes clearance in cells from LSD patients and in murine models of LSDs. The goal of this project is to develop novel methods to modulate lysosomal function via TFEB and through TFEB independent pathways, the results will represent a paradigm shift in the treatment of LSDs and will also impact the therapy of many common, late onset, neurodegenerative proteinopathies. .
| Napolitano, Gennaro; Esposito, Alessandra; Choi, Heejun et al. (2018) mTOR-dependent phosphorylation controls TFEB nuclear export. Nat Commun 9:3312 |
| Pastore, Nunzia; Vainshtein, Anna; Klisch, Tiemo J et al. (2017) TFE3 regulates whole-body energy metabolism in cooperation with TFEB. EMBO Mol Med 9:605-621 |
| Di Malta, Chiara; Siciliano, Diletta; Calcagni, Alessia et al. (2017) Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science 356:1188-1192 |
| Bartolomeo, Rosa; Cinque, Laura; De Leonibus, Chiara et al. (2017) mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. J Clin Invest 127:3717-3729 |
| Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222 |
| Ballabio, Andrea (2016) The awesome lysosome. EMBO Mol Med 8:73-6 |
| Calcagnì, Alessia; Kors, Lotte; Verschuren, Eric et al. (2016) Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling. Elife 5: |
| Pastore, Nunzia; Brady, Owen A; Diab, Heba I et al. (2016) TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages. Autophagy 12:1240-58 |
| Martini-Stoica, Heidi; Xu, Yin; Ballabio, Andrea et al. (2016) The Autophagy-Lysosomal Pathway in Neurodegeneration: A TFEB Perspective. Trends Neurosci 39:221-234 |
| Lapierre, Louis R; Kumsta, Caroline; Sandri, Marco et al. (2015) Transcriptional and epigenetic regulation of autophagy in aging. Autophagy 11:867-80 |
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