Birt-Hogg-Dubé（BHD）综合症是一种遗传性家族癌症综合症，因编码肿瘤抑制蛋白folliculin（FLCN）的基因的损失功能致病性变异引起，以皮肤病变、肺囊肿、肾肿瘤和囊肿为特征。FLCN作为溶酶体生物合成和自噬的主控制器TFEB和TFE3转录因子的负调节因子，通过使它们在机械靶向雷帕霉素复合物1（mTORC1）的磷酸化。我们先前已经表明，Tfeb的删除拯救了肾特异性Flcn KO小鼠的肾囊性表型。使用Flcn/Tfeb/Tfe3双重和三重KO小鼠，我们现在表明，Tfeb和Tfe3以不同和协同的方式促进肾囊肿形成。值得注意的是，对BHD患者衍生的肿瘤样本的分析揭示了TFEB/TFE3介导的转录程序的增加活化，并且沉默这两个基因可拯救BHD人类肾肿瘤细胞系衍生的异种移植瘤（CDX）中的肿瘤形成。我们的发现在与疾病相关的模型中表明，TFEB和TFE3都是肾肿瘤发生的关键驱动因素，并暗示了基于这些转录因子抑制的新型治疗策略。©2023作者。以CC BY 4.0许可证条款发表。

Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.