The lysosome has always been viewed as a “static” organelle that performs “housekeeping” functions. Discoveries from our laboratory have challenged this view by revealing that the lysosome is a dynamic structure subject to a global transcriptional regulatory network able to adapt lysosomal function to environmental cues. We identified the transcription factor TFEB as the master regulator of this transcriptional program (Science 2009, 325(5939):473-7). Importantly, we demonstrated that induction of lysosomal biogenesis and autophagy via TFEB is a potent tool to promote cellular clearance (Science 2011, 332(6036):1429-33; Dev Cell 2011, 3;21(3):421-30). Over the last decade, we have also contributed to the elucidation of the mechanisms by which TFEB activation is modulated. We discovered that TFEB subcellular localization and activity are regulated by the mTORC1 kinase through a lysosome-to-nucleus signaling mechanism (EMBO J. 2012, 31:1095). This regulatory pathway allows the lysosome to respond to environmental cues such as starvation, physical exercise, infection, and a variety of stress conditions. We also have identified a feedback loop mechanism by which TFEB is not only a substrate but also a regulator of mTORC1, by promoting the expression of RagC/D GTPases (Science 2017, 356(6343):1188-1192). We discovered that in cancer, this feedback loop enables cellular adaptation to nutrient availability and supports the energy-demanding metabolism of cancer cells. More recently we showed that TFEB phosphorylation by mTORC1, unlike the “canonical” mTORC1 substrates S6K and 4E-BP1, is regulated through a specific substrate-recruitment mechanism that is mediated by RagGTPase/TFEB interaction. We revealed that this mechanism has a crucial role in Birt–Hogg–Dubé syndrome, a rare inherited cancer syndrome that is caused by mutations in the RagC/D activator folliculin (FLCN) and that TFEB is the main driver of renal cysts and cancer in this disease (Nature 2020, 585:597–602).
Many biological questions remain and are the object of our current and future research: Which stimuli and proteins activate the TFEB-substrate-specific mechanism? What molecular and metabolic programs downstream of dysregulated mTORC1-TFEB signaling pathway are key to the development of human diseases? How can we target the mTORC1-TFEB pathway for therapeutic purposes?
We are tackling these questions by using ‘omic’, in vitro and in vivo approaches.

PostDoc and Research Fellows: Jlenia Monfregola, Irene Sambri, Marco Ferniani, Marcella Cesana
Ph.D. Student: Gennaro Tufano, Claudia Vilardo
Technician:  Fabrizio Andreone, Barbara Rossi, Nicolina Zampelli, Rossella Pennella

Lab Manager: Floriana Forzati

1. A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome. Nature, 2020
2. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science, 2017
3. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosomes via mTOR and TFEB. The EMBO Journal, 2012
4. TFEB Links Autophagy to Lysosomal Biogenesis. Science, 2011
5. A Gene Network Regulating Lysosomal Biogenesis and Function. Science, 2009

Complete List of Published Work of more than 360 publications in My Bibliography

The Baylor College of Medicine
The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital