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

Iris E. Glykofridis, Jaco C. Knol, Jesper A. Balk, Denise Westland, Thang V. Pham, Sander R. Piersma, Sinéad M. Lougheed, Sepide Derakhshan, Puck Veen, Martin A. Rooimans, Saskia E. van Mil, Franziska Böttger, Pino J. Poddighe, Irma van de Beek, Jarno Drost, Fried J. T. Zwartkruis, Renee X. de Menezes, Hanne E. J. Meijers-Heijboer, Arjan C. Houweling, Connie R. Jimenez*Rob M. F. Wolthuis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Article numbere61630
Pages (from-to)1-71
Number of pages71
Publication statusPublished - 1 Jan 2021

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