Michel Alchoueiry, MD,MSc
Pulmonary and Clinical Care Medicine
Michel Alchoueiry*, Damir Khabibullin, Nicola Alesi, Pieter Cory, Elizabeth Henske
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant inherited disorder caused by germline loss-of-function mutations in the Folliculin gene (FLCN). BHD can cause benign tumors of the hair follicle called fibrofolliculomas, lung cysts, spontaneous pneumothorax, and kidney tumors. Between 16 and 34% of BHD patients develop renal cell carcinoma at the average age of 50 years.
FLCN and its interacting partners, FNIP1 and FNIP2, cooperatively play important roles in metabolic pathways including the regulation of lysosome biogenesis and function through control of the nuclear localization of the transcription factors TFEB and TFE3. The dysregulation of these metabolic pathways triggers aberrant kidney cell proliferations and renal tumorigenesis. Recently Transcription Factor EB (TFEB), was discovered to be a major driver of the kidney cysts/tumors in a mouse model of BHD. Lysosome biogenesis and lysosomal exocytosis are directly regulated by TFEB.
Lysosomal exocytosis is critical for normal processes, such as plasma membrane repair, bone resorption by osteoclasts, melanin deposition by melanocytes, immune response against parasitic attack and antigen presentation. In tumor cells, lysosomal exocytosis is believed to enhance invasion and progression by digesting and remodeling the extracellular matrix. Lysosomal exocytosis is a calcium-dependent process. The efflux of calcium is mediated by Mucolipin-1 (MCOLN1), a cation channel. Lysosomal exocytosis is decreased in cells lacking MCOLN1 and increased in cells expressing a gain of function MCOLN1 mutation.
We are currently investigating these pathways in models of BHD. We have found that MCOLN1 levels are elevated in FLCN-deficient cells compared to wildtype cells. We also found that lysosomal enzymes are increased in FLCN-deficient cells and that Vacuolin1, which inhibits lysosomal exocytosis blocks the proliferation of FLCN-deficient cells to a greater extent than the control cells. In future work, we will determine whether and how lysosomal exocytosis contributes to the progression of renal carcinoma growth in BHD.
We expect this project to have scientific impact by elucidating the mechanisms through which FLCN-deficiency leads to renal tumors, including the role of MCOLN1 in lysosome-mediated exocytosis in BHD, and clinical impact by revealing novel therapeutic targets for BHD-associated RCC. We note that while this proposal is focused on the kidney, we suspect that similar lysosomal-exocytosis mechanisms contribute to cystic lung disease in BHD, which will be addressed in future studies.