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FLCN-FNIP1/2 的缺失会在人肾小管上皮细胞中诱导非经典的干扰素反应。

Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells.

机构信息

Amsterdam UMC, location VUmc, Vrije Universiteit Amsterdam, Clinical Genetics, Cancer Center Amsterdam, Amsterdam, Netherlands.

Amsterdam UMC, location VUmc, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.

出版信息

Elife. 2021 Jan 18;10:e61630. doi: 10.7554/eLife.61630.

DOI:10.7554/eLife.61630
PMID:33459596
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7899648/
Abstract

Germline mutations in the Folliculin () tumor suppressor gene cause Birt-Hogg-Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing carriers to kidney tumors. is a conserved, essential gene linked to diverse cellular processes but the mechanism by which prevents kidney cancer remains unknown. Here, we show that disrupting in human renal tubular epithelial cells (RPTEC/TERT1) activates TFE3, upregulating expression of its E-box targets, including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, the absence of FLCN or its binding partners FNIP1/FNIP2 induces interferon response genes 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 immune responses. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.

摘要

种系突变滤泡素 () 肿瘤抑制基因导致伯-霍格-杜布综合征 (BHD)，一种罕见的常染色体显性遗传疾病，使携带者易患肾肿瘤。 是一个保守的、必需的基因，与多种细胞过程有关，但 防止肾癌的机制尚不清楚。在这里，我们表明，破坏人类肾小管上皮细胞 (RPTEC/TERT1) 中的 会激活 TFE3，上调其 E 盒靶基因的表达，包括 RRAGD 和 GPNMB，而不改变 mTORC1 活性。令人惊讶的是，FLCN 或其结合伴侣 FNIP1/FNIP2 的缺失会独立于干扰素诱导干扰素反应基因。从机制上讲，FLCN 的缺失促进了 STAT2 向染色质的募集，并减缓了细胞增殖。我们的综合分析确定了 STAT1/2 信号作为肾脏细胞和 BHD 肿瘤中 FLCN 的一个新靶点。STAT1/2 的激活似乎可以抵消 TFE3 介导的过度增殖，并可能影响免疫反应。这些发现揭示了 FLCN 在人类肾肿瘤发生中的独特作用，并指出了候选的预后生物标志物。

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