For years, TFEB has been regarded as one of the most promising therapeutic targets for restoring the cell's ability to clear and recycle waste. Yet turning that promise into therapies has proved difficult, because TFEB itself is hard to target with drugs. Now, a study published in Nature by scientists at the Telethon Institute of Genetics and Medicine (TIGEM) has identified a molecular pathway that controls TFEB activity, uncovering new druggable targets that could open the door to therapies for rare genetic diseases, cancer and other conditions linked to lysosomal dysfunction.
Lysosomes act as the cell's recycling centres. When they stop working properly, waste accumulates inside cells, contributing to a growing number of disorders, including lysosomal storage diseases, neurodegenerative conditions and some cancers.
Over the past fifteen years, TFEB has emerged as a master regulator of the genes that keep this recycling system running. Because activating TFEB boosts the cell's ability to remove damaged material and adapt to stress, scientists have long considered it an attractive therapeutic target. But there has been a major obstacle: transcription factors such as TFEB are notoriously difficult to drug.
The new study, coordinated by Gennaro Napolitano at TIGEM, points to a possible way around that problem. Rather than targeting TFEB directly, the researchers identified the molecular machinery that switches it on, revealing new targets that could be manipulated pharmacologically. The work involved collaborators at University of Fribourg (Switzerland), UC Berkeley (USA), University of Rome "Tor Vergata" (Italy) and German Cancer Research Center (DKFZ, Germany). The study was supported primarily by Fondazione Telethon and Fondazione AIRC (Italian Association for cancer Research).
A new route to TFEB activation
The study builds on a field pioneered by former TIGEM Scientific Director Andrea Ballabio , whose research in 2009 first established TFEB as a master regulator of lysosomal function and cellular clearance. TFEB is a transcription factor that controls the expression of genes involved in lysosomal biogenesis and autophagy, the cellular processes responsible for breaking down and recycling damaged components.
TFEB has soon become a major focus of biomedical research because enhancing its activity could help restore cellular health in diseases characterized by the accumulation of harmful material inside cells. Few discoveries in lysosomal biology have had such a profound impact on the field: so far nearly 3,000 scientific publications have been focused on TFEB, with more than 90% of them published in the last decade. TFEB has attracted growing interest as a potential therapeutic target in a wide range of experimental disease models, including lysosomal storage disorders, Parkinson's disease, obesity and cancer. It is also among the priority targets identified by the Michael J. Fox Foundation's Targets to Therapies initiative for Parkinson's disease.
Yet despite this excitement, no therapy specifically designed to activate TFEB has reached the clinic so far, making the search for new ways to control its activity a major goal for the field. What remained unclear was how cells detect lysosomal perturbations and respond by activating TFEB.
Napolitano and colleagues found that lysosomal stress triggers the activation of two enzymes, TBK1 and ULK1. Once activated, these enzymes modify a protein called FNIP1, setting off a chain of events that allows TFEB to move into the nucleus and switch on genes involved in cellular recycling and lysosomal function. The process starts at the lysosomal proton pump v-ATPase and involves the adaptor protein TAX1BP1.
"Researchers have known for years that TFEB plays a fundamental role in helping cells maintain their recycling machinery and adapt to stress. What remained unclear was how cells sense lysosomal dysfunction and translate that signal into TFEB activation. Our work identifies the molecular players involved in this process and reveals a signaling pathway that had never been described before," says Alessandra Esposito, first author of the study.
New avenues for future therapies
The researchers also explored the role of the pathway in follicular lymphoma, a blood cancer in which mutations affecting the v-ATPase component ATP6V1B2 are relatively common. They showed that these mutations lead to persistent activation of TFEB, helping tumor cells survive and grow in nutrient-poor environments.
But the implications of the discovery extend well beyond cancer.
Boosting TFEB activity has long been considered a promising strategy for treating a range of rare genetic diseases caused by lysosomal dysfunction, as well as other disorders characterized by the build-up of toxic material inside cells. Until now, however, researchers lacked practical ways to modulate the pathway.
"Rather than targeting TFEB itself, our study identifies molecular regulators that control its activation. This provides new entry points for the development of therapeutic strategies aimed at harnessing TFEB activity in disease," says Alessandra Esposito.
"The identification of the TBK1/ULK1 pathway expands the therapeutic opportunities for modulating TFEB," says Gennaro Napolitano, lead investigator of the study. "Because this mechanism acts upstream of TFEB, it could offer new opportunities not only in TFEB-dependent cancers but also in a broader spectrum of diseases where improving lysosomal function may be beneficial."
By uncovering druggable targets upstream of TFEB, the study brings researchers a step closer to translating years of discoveries in lysosomal biology into new therapies for rare genetic diseases and other conditions.
