Our long-term goal is to define how lysosome activity is regulated and to use this understanding to develop strategies to modulate lysosomal function for therapeutic purposes. Lysosomes perform critical functions with regard to the cellular degradation of macromolecules and the recycling of the nutrients that are liberated by this process. The transcription factor TFEB has been identified as a major regulator of genes encoding lysosomal proteins. Thus, the signaling mechanisms that regulate TFEB activity could contribute to the overall control of lysosome homeostasis. This project focuses on the role played by folliculin, the Birt-Hogg-Dub? syndrome gene, and its binding partner folliculin interacting protein 1 (FNIP1) in this process. The proposed research builds on our novel observations that FLCN and FNIP1 localize to lysosomes and have a strong influence on regulating the nuclear levels of TFEB. Both the AMPK and mTORC1 signaling pathways that are related to cellular energy and nutrient homeostasis respectively may play a role in this action of FLCN and FNIP1. Our proposed research seeks to understand: 1) the role for TFEB as a FLCN and FNIP1 effector in the regulation of lysosome function;2) the basis for the recruitment of folliculin and FNIP1 to lysosomes;3) the physical interactions between FLCN, FNIP1 and AMPK and their effects on the recruitment of this kinase to the surface of lysosomes;and 4) the FLCN and FNIP1-dependent regulation of mTORC1 activation at the cytoplasmic surface of lysosomes. These studies will take advantage of our expertise in live cell imaging, protein-protein and protein-membrane interactions to analyze the dynamic recruitment of FLCN, FNIP1 and their binding partners to the cytoplasmic surface of lysosomes and the relationship of such recruitment to their function. This research builds on a growing appreciation of the role played by degradation and recycling of lysosomal substrates for meeting the energy and nutrient demands of cells and also highlights possible opportunities for the enhancement of lysosome function that could be relevant for the treatment of neurodegenerative diseases.

Public Health Relevance

Strategies to enhance the cellular degradation of protein aggregates and damaged organelles could be broadly applicable of a wide range of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and lysosomal storage disorders. Conversely, it is becoming increasingly appreciated that abnormally high rates of macromolecule breakdown and nutrient recycling help to provide some cancers with the building blocks that support tumor growth and metastasis. Our research is directly relevant to the mission of the NIH as it aims to identify novel strategies for regulating the ability of cells o degrade macromolecules that could lead to novel treatments for these diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Membrane Biology and Protein Processing (MBPP)
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Ainsztein, Alexandra M
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Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
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Puertollano, Rosa; Ferguson, Shawn M; Brugarolas, James et al. (2018) The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. EMBO J 37:
Ferguson, Shawn M (2018) Axonal transport and maturation of lysosomes. Curr Opin Neurobiol 51:45-51
Meng, Jin; Ferguson, Shawn M (2018) GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. J Cell Biol 217:2765-2776
Nguyen, Andrew D; Nguyen, Thi A; Zhang, Jiasheng et al. (2018) Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay. Proc Natl Acad Sci U S A 115:E2849-E2858
Amick, Joseph; Tharkeshwar, Arun Kumar; Amaya, Catherine et al. (2018) WDR41 supports lysosomal response to changes in amino acid availability. Mol Biol Cell 29:2213-2227
Ferguson, Shawn M (2018) Neuronal lysosomes. Neurosci Lett :
Amick, Joseph; Ferguson, Shawn M (2017) C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. Traffic 18:267-276
Gowrishankar, Swetha; Wu, Yumei; Ferguson, Shawn M (2017) Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology. J Cell Biol 216:3291-3305
Gowrishankar, Swetha; Ferguson, Shawn M (2016) Lysosomes relax in the cellular suburbs. J Cell Biol 212:617-9
Amick, Joseph; Roczniak-Ferguson, Agnes; Ferguson, Shawn M (2016) C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Mol Biol Cell 27:3040-3051

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