Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells
- Amsterdam UMC, Netherlands
- University Medical Center Utrecht, Netherlands
- Princess Máxima Center for Pediatric Oncology, Netherlands
- NKI-AvL, Netherlands
Abstract
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.
Data availability
Data files of transcriptomic and proteomic data are provided as supplementary table 1. Raw data files deposited on Dryad Digital Repository (RNAseq): doi:10.5061/dryad.6djh9w0zsProteomeXchange (Mass Spec) under accession number PXD021346
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RNAseq raw counts_FLCN positive vs. FLCN negative RPTECsDryad Digital Repository, doi:10.5061/dryad.6djh9w0zs.
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Mass Spec data_FLCN positive vs. FLCN negative RPTECsProteomeXchange, PXD021346.
Article and author information
Author details
Iris E Glykofridis
Funding
KWF Kankerbestrijding/Alpe d'Huzes Bas Mulder Award
- Jarno Drost
Foundation Children Cancer Free (Core Funding)
- Sepide Derakhshan
Oncode Institute
- Jarno Drost
Cancer Center Amsterdam (CCA2018-5-51)
- Iris E Glykofridis
- Rob MF Wolthuis
Cancer Center Amsterdam (Core Funding Mass Spectrometry Infrastructure)
- Jaco C Knol
- Thang V Pham
- Sander R Piersma
- Connie R Jimenez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: BHD T1 and BHD T2 tumor samples were obtained with informed consent. Both tissues are leftover material from surgery and are stored in our BHD biobank (2019.359 at AmsterdamUMC).
Copyright
© 2021, Glykofridis et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells
eLife 10:e61630.
https://doi.org/10.7554/eLife.61630
