TY - JOUR
T1 - Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells
AU - Glykofridis, Iris E.
AU - Knol, Jaco C.
AU - Balk, Jesper A.
AU - Westland, Denise
AU - Pham, Thang V.
AU - Piersma, Sander R.
AU - Lougheed, Sinéad M.
AU - Derakhshan, Sepide
AU - Veen, Puck
AU - Rooimans, Martin A.
AU - van Mil, Saskia E.
AU - Böttger, Franziska
AU - Poddighe, Pino J.
AU - van de Beek, Irma
AU - Drost, Jarno
AU - Zwartkruis, Fried J. T.
AU - de Menezes, Renee X.
AU - Meijers-Heijboer, Hanne E. J.
AU - Houweling, Arjan C.
AU - Jimenez, Connie R.
AU - Wolthuis, Rob M. F.
N1 - Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
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UR - https://www.ncbi.nlm.nih.gov/pubmed/33459596
U2 - https://doi.org/10.7554/eLife.61630
DO - https://doi.org/10.7554/eLife.61630
M3 - Article
C2 - 33459596
SN - 2050-084X
VL - 10
SP - 1
EP - 71
JO - eLife
JF - eLife
M1 - e61630
ER -