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 Jt Zwartkruis, Renee X de Menezes, Hanne Ej Meijers-Heijboer, Arjan C Houweling, Connie R JimenezRob Mf Wolthuis

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Germline mutations in the Folliculin (FLCN) tumor suppressor gene cause Birt-Hogg-Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing carriers to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanism by which FLCN prevents kidney cancer remains unknown. Here, we show that disrupting FLCN 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.

Original languageEnglish
Article numbere61630
Pages (from-to)1-71
Number of pages71
JournaleLife
Volume10
DOIs
Publication statusPublished - 18 Jan 2021
Externally publishedYes

Keywords

  • Carrier Proteins/genetics
  • Epithelial Cells/metabolism
  • Germ-Line Mutation
  • Humans
  • Interferons/metabolism
  • Kidney/metabolism
  • Proto-Oncogene Proteins/genetics
  • Tumor Suppressor Proteins/genetics

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