RNAseq raw counts FLCN positive vs. FLCN negative renal proximal tubular epithelial cells (RPTEC)

Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé
(BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney
tumors. FLCN is a conserved, essential gene linked to diverse cellular
processes but the mechanisms by which FLCN prevents kidney cancer remain
unknown. Here we show that deleting FLCN activates TFE3, upregulating its
downstream E-box genes in human renal tubular epithelial cells
(RPTEC/TERT1), including RRAGD and GPNMB, without modifying mTORC1
activity. Surprisingly, deletion of FLCN or its binding partners
FNIP1/FNIP2 also induces interferon response genes, but independently of
interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to
chromatin and slows cellular proliferation. Our integrated analysis
identifies STAT1/2 signaling as a novel target of FLCN in renal cells and
BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed
hyper-proliferation and may influence the immune response. These findings
shed light on unique roles of FLCN in human renal tumorigenesis and
pinpoint candidate prognostic biomarkers.