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.

中文翻译：

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FLCN-FNIP1/2 的缺失在人肾小管上皮细胞中诱导非经典干扰素反应

卵泡蛋白 (FLCN) 的种系失活突变导致 Birt-Hogg-Dubé (BHD) 综合征，这是一种罕见的常染色体显性遗传疾病，易患肾肿瘤。FLCN 是与多种细胞过程相关的保守的必需基因，但 FLCN 预防肾癌的机制仍然未知。在这里，我们显示删除 FLCN 激活 TFE3，上调人肾小管上皮细胞 (RPTEC/TERT1) 中的下游 E-box 基因，包括 RRAGD 和 GPNMB，而不改变 mTORC1 活性。令人惊讶的是，FLCN 或其结合伙伴 FNIP1/FNIP2 的缺失也会诱导干扰素反应基因，但与干扰素无关。从机制上讲，FLCN 缺失促进 STAT2 募集到染色质并减缓细胞增殖。我们的综合分析将 STAT1/2 信号转导确定为肾细胞和 BHD 肿瘤中 FLCN 的新靶点。STAT1/2 激活似乎抵消了 TFE3 导向的过度增殖，并可能影响免疫反应。这些发现揭示了 FLCN 在人肾肿瘤发生中的独特作用，并确定了候选预后生物标志物。