Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

// Katsuyuki Nagashima 1, 2, 6 , Hidefumi Fukushima 1 , Kouhei Shimizu 3 , Aya Yamada 4 , Masumi Hidaka 2 , Hisashi Hasumi 5 , Tetsuro Ikebe 6 , Satoshi Fukumoto 1, 4 , Koji Okabe 2 , Hiroyuki Inuzuka 1, 3 1 Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan 2 Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan 3 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA 4 Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan 5 Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan 6 Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka 814-0193, Japan Correspondence to: Hiroyuki Inuzuka, email: hinuzuka@bidmc.harvard.edu Hidefumi Fukushima, email: hidefumi.fukushima.b7@tohoku.ac.jp Keywords: FNIP, FLCN, tumor suppressor, β-TRCP, renal cancer Received: October 11, 2016      Accepted: November 22, 2016      Published: December 25, 2016 ABSTRACT Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dube (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCF β-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer.