sorce data.xlsx

RNF214 is an understudied ubiquitin ligase without any knowledge of its biological functions orprotein substrates. Here we show that the TEAD transcription factorsin the Hippo pathway are substrates of RNF214. RNF214 inducesnon-proteolytic ubiquitylation at a conservedlysineresidueof TEADs,enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling.Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a new signaling axis of RNF214-TEAD-YAPand suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy.

RNF214是一种研究尚不充分的泛素连接酶，目前其生物学功能及蛋白质底物均尚未明确。本研究证实，Hippo信号通路中的TEAD转录因子为RNF214的底物。RNF214可在TEAD家族蛋白的保守赖氨酸残基处介导非蛋白降解型泛素化修饰，增强TEAD与YAP的相互作用，并促进Hippo信号通路下游基因的转录激活。此外，YAP与TAZ可结合多聚泛素链，这提示了RNF214调控Hippo通路的潜在分子机制。进一步研究发现，RNF214在肝细胞癌（HCC）组织中呈高表达，且与肿瘤分化程度及患者生存期呈负相关。功能实验一致表明，RNF214可促进肿瘤细胞的增殖、迁移与侵袭，并在小鼠体内促进肝细胞癌的发生发展。综上，本研究数据揭示RNF214通过形成RNF214-TEAD-YAP全新信号轴，成为Hippo通路的关键调控组分；同时证实RNF214是肝细胞癌的致癌基因，有望成为肝细胞癌治疗的潜在药物靶点。