SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development.
SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development.
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DOI：
10.15252/embj.201593374
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发表时间：
2016-07-01
期刊：
影响因子：
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通讯作者：
D'Angiolella V
中科院分区：
文献类型：
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作者：
Raducu M;Fung E;Serres S;Infante P;Barberis A;Fischer R;Bristow C;Thézénas ML;Finta C;Christianson JC;Buffa FM;Kessler BM;Sibson NR;Di Marcotullio L;Toftgård R;D'Angiolella V
Skp1-Cul1-F-box蛋白(SCF)泛素连接酶通过控制蛋白质泛素化和降解，直接决定细胞的存活。Sufu(融合抑制因子)是HH(Hedgehog)信号的中央调节因子，通过使Gliomatedoncogene Homolog(胶质瘤相关癌基因同源)转录因子失活而发挥肿瘤抑制作用。尽管Sufu在HH信号中起着关键作用，但参与控制Sufu水平的参与者及其在肿瘤生长中的作用尚不清楚。在这里，我们证明了Fbxl17(F-box和富含亮氨酸的重复蛋白17)在细胞核内以Sufu为靶点进行蛋白质分解。Sufu的泛素化由Fbxl17介导，允许从Sufu释放Gli1，以进行适当的HH信号转导。Fbxl17的缺失导致HH信号缺陷，与癌细胞增殖受损和髓母细胞瘤生长相关。此外，我们在Gorlin综合征患者的髓母细胞瘤中发现了Sufu的突变，该突变通过Fbxl17介导的多泛素化增加Sufu的周转，并导致持续的HH信号激活。综上所述，我们的发现揭示了Fbxl17是一种新的HH途径调节因子，并强调了Fbxl17-Sufu轴在髓母细胞瘤发病机制中的扰动。
Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.