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 Jimenez; Rob Mf Wolthuis

doi:10.7554/eLife.61630

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

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

15 Citaten (Scopus)

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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.

Originele taal-2	Engels
Artikelnummer	e61630
Pagina's (van-tot)	1-71
Aantal pagina's	71
Tijdschrift	eLife
Volume	10
DOI's	https://doi.org/10.7554/eLife.61630
Status	Gepubliceerd - 18 jan. 2021
Extern gepubliceerd	Ja

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10.7554/eLife.61630

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Glykofridis, I. E., Knol, J. C., Balk, J. A., Westland, D., Pham, T. V., Piersma, S. R., Lougheed, S. M., Derakhshan, S., Veen, P., Rooimans, M. A., van Mil, S. E., Böttger, F., Poddighe, P. J., van de Beek, I., Drost, J., Zwartkruis, F. J., de Menezes, R. X., Meijers-Heijboer, H. E., Houweling, A. C., ... Wolthuis, R. M. (2021). Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells. eLife, 10, 1-71. Artikel e61630. https://doi.org/10.7554/eLife.61630

@article{bdec09dfe34b4ceb88e4d74ee2d4fd0c,

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

abstract = "Germline mutations in the Folliculin (FLCN) tumor suppressor gene cause Birt-Hogg-Dub{\'e} (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.",

keywords = "Carrier Proteins/genetics, Epithelial Cells/metabolism, Germ-Line Mutation, Humans, Interferons/metabolism, Kidney/metabolism, Proto-Oncogene Proteins/genetics, Tumor Suppressor Proteins/genetics",

author = "Glykofridis, {Iris E} and Knol, {Jaco C} and Balk, {Jesper A} and Denise Westland and Pham, {Thang V} and Piersma, {Sander R} and Lougheed, {Sin{\'e}ad M} and Sepide Derakhshan and Puck Veen and Rooimans, {Martin A} and {van Mil}, {Saskia E} and Franziska B{\"o}ttger and Poddighe, {Pino J} and {van de Beek}, Irma and Jarno Drost and Zwartkruis, {Fried Jt} and {de Menezes}, {Renee X} and Meijers-Heijboer, {Hanne Ej} and Houweling, {Arjan C} and Jimenez, {Connie R} and Wolthuis, {Rob Mf}",

note = "{\textcopyright} 2021, Glykofridis et al.",

year = "2021",

month = jan,

day = "18",

doi = "10.7554/eLife.61630",

language = "English",

volume = "10",

pages = "1--71",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

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Glykofridis, IE, Knol, JC, Balk, JA, Westland, D, Pham, TV, Piersma, SR, Lougheed, SM, Derakhshan, S, Veen, P, Rooimans, MA, van Mil, SE, Böttger, F, Poddighe, PJ, van de Beek, I, Drost, J, Zwartkruis, FJ, de Menezes, RX, Meijers-Heijboer, HE, Houweling, AC, Jimenez, CR & Wolthuis, RM 2021, 'Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells', eLife, vol. 10, e61630, blz. 1-71. https://doi.org/10.7554/eLife.61630

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 Jt

AU - de Menezes, Renee X

AU - Meijers-Heijboer, Hanne Ej

AU - Houweling, Arjan C

AU - Jimenez, Connie R

AU - Wolthuis, Rob Mf

PY - 2021/1/18

Y1 - 2021/1/18

N2 - 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.

AB - 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.

KW - Carrier Proteins/genetics

KW - Epithelial Cells/metabolism

KW - Germ-Line Mutation

KW - Humans

KW - Interferons/metabolism

KW - Kidney/metabolism

KW - Proto-Oncogene Proteins/genetics

KW - Tumor Suppressor Proteins/genetics

UR - http://www.scopus.com/inward/record.url?scp=85100200292&partnerID=8YFLogxK

U2 - 10.7554/eLife.61630

DO - 10.7554/eLife.61630

M3 - Article

C2 - 33459596

SN - 2050-084X

VL - 10

SP - 1

EP - 71

JO - eLife

JF - eLife

M1 - e61630

ER -

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

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