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Loss of FLCN-FNIP1/2 Induces a Non-Canonical Interferon 1 Response in Human Renal Tubular Epithelial Cells

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 that has been linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown Here we show that FLCN loss activates E-box target genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD, yet without modifying mTORC1 activity. Surprisingly, inactivation of FLCN or its binding partners FNIP1/FNIP2 activates interferon response genes but independently of interferon. Mechanistically, FLCN loss promotes recruitment of STAT2 to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 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 novel prognostic biomarkers.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney Proximal Straight Tubule Epithelial Cell

DISEASE(S): Renal Cell Carcinoma

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD021346 | Pride | 2021-02-11

REPOSITORIES: Pride

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	QE1_170706_OPL2039_IG_FLCN_kd_A1.raw	Raw
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Project description:In Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive complete phosphoproteomic profiles of FLCNPOS and FLCNNEG human renal tubular epithelial cells (RPTEC/TERT1). In total, 15744 phosphorylated peptides were identified, residing on 4329 phosphorylated proteins. Kinase activity inference analysis revealed that FLCN loss elevates phosphorylation of numerous kinases, including tyrosine kinases EPHA2 and MET, as well as activation of downstream MAPK1/3/6 and 8. Three non-canonical phosphorylation sites on EGFR (Tyr1125, Tyr1138 and Tyr1172) were higher phosphorylated upon FLCN loss together with enhanced phosphorylated EGFR substrates ABI, EPS8, ERRFL1, STAT1, PTK2 and CTNND1. In concordance, phosphosite specific signature analyses revealed an enrichment for EGFR signaling in FLCNNEG cells. Interestingly, we detected FLCN dependent phosphorylation of PIK3CD but no canonical downstream Akt/mTOR activation. In agreement with the induction of the E-box transcriptional gene expression signature upon FLCN loss, here we identified that phosphorylation of TFEB on Ser109, Ser114 and Ser122 is dependent on FLCN and absence of this phosphorylation results in constitutive nuclear localization of this transcription factor in FLCNNEG cells. Together, our study reveals enhanced phosphorylation of specific kinases and substrates in FLCNNEG renal epithelial cells, providing important insights in BHD-associated renal tumorigenesis and offering novel handles for the design of targeted therapies.

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