Abstract
Birt-Hogg-Dube (BHD) is a tumor suppressor gene syndrome associated with fibrofolliculomas, cystic lung disease, and chromophobe renal cell carcinoma. In seeking to elucidate the pathogenesis of BHD, we discovered a physical interaction between folliculin (FLCN), the protein product of the BHD gene, and p0071, an armadillo repeat containing protein that localizes to the cytoplasm and to adherens junctions. Adherens junctions are one of the three cell-cell junctions that are essential to the establishment and maintenance of the cellular architecture of all epithelial tissues. Surprisingly, we found that downregulation of FLCN leads to increased cell-cell adhesion in functional cell-based assays and disruption of cell polarity in a three-dimensional lumen-forming assay, both of which are phenocopied by downregulation of p0071. These data indicate that the FLCN-p0071 protein complex is a negative regulator of cell-cell adhesion. We also found that FLCN positively regulates RhoA activity and Rho-associated kinase activity, consistent with the only known function of p0071. Finally, to examine the role of Flcn loss on cell-cell adhesion in vivo, we utilized keratin-14 cre-recombinase (K14-cre) to inactivate Flcn in the mouse epidermis. The K14-Cre-Bhdflox/flox mice have striking delays in eyelid opening, wavy fur, hair loss, and epidermal hyperplasia with increased levels of mammalian target of rapamycin complex 1 (mTORC1) activity. These data support a model in which dysregulation of the FLCN-p0071 interaction leads to alterations in cell adhesion, cell polarity, and RhoA signaling, with broad implications for the role of cell-cell adhesion molecules in the pathogenesis of human disease, including emphysema and renal cell carcinoma.
Highlights
Cell-cell junctions, which include adherens junctions, desmosomes, and tight junctions, are fundamental to the intricate cellular architecture of all epithelial tissues [1]
Germline mutations of the BHD gene, which is on chromosome 17p11.2 and was cloned in 2002 [13], lead to an autosomal dominant disease associated with fibrofolliculomas, cystic lung disease, which can result in spontaneous pneumothorax, and renal cell carcinomas (RCC), which are most often of the chromophobe subtype
We report here that FLCN interacts with the adherens junction protein p0071 to regulate cell-cell adhesion, cell migration, cell polarity, and RhoA signaling
Summary
Cell-cell junctions, which include adherens junctions, desmosomes, and tight junctions, are fundamental to the intricate cellular architecture of all epithelial tissues [1]. Germline mutations of the BHD gene, which is on chromosome 17p11.2 and was cloned in 2002 [13], lead to an autosomal dominant disease associated with fibrofolliculomas (benign skin tumors), cystic lung disease, which can result in spontaneous pneumothorax (lung collapse), and renal cell carcinomas (RCC), which are most often of the chromophobe subtype. The penetrance of these phenotypes is incomplete: 15–30% of BHD patients develop RCC [14], and families have been reported in which cystic lung disease and pneumothorax occur in the absence of renal or skin manifestations [15,16,17,18]. Dysregulation of the FLCN-p0071 interaction may underlie the unusual triad of lung, skin, and renal manifestations in BHD patients, and could have critical implications for the pathogenesis of cystic lung disease and chromophobe renal cell carcinoma in the general population
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