Mof4 family associated protein 1 (MRFAP1) is a 14 kDa nuclear protein, which involves in maintaining normal histone modification levels by negatively regulating recruitment of the NuA4 (nucleosome acetyltransferase of H4) histone acetyltransferase complex to chromatin. MRFAP1 has been identified as one of the most up-regulated proteins after NEDD8 (neural precursor cell expressed developmentally down-regulated 8) inhibition in multiple human cell lines. However, the biological function of MRFAP1 and the E3 ligase that targets MRFAP1 for destruction remain mysterious. Here we show, by using an immunoprecipitation-based proteomics screen, that MRFAP1 is an interactor of the F-box protein FBXW8. MRFAP1 is degraded by means of the ubiquitin ligase Cul7/FBXW8 during mitotic anaphase-telophase transition and accumulated in mitotic metaphase. Overexpression of FBXW8 increased the polyubiquitination and decreased the stability of MRFAP1, whereas knockdown of FBXW8 prolonged the half-life of MRFAP1. Moreover, forced expression of MRFAP1 in HeLa cells caused growth retardation and genomic instability, leading to severe mitotic cell death. Thus, Cul7/FBXW8-mediated destruction of MRFAP1 is a regulatory component monitoring the anaphase-telophase transition and preventing genomic instability.
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This study is supported by grants from the Natural Science Foundation of China (81773018, 31401185, 81570769 and 81602626), Natural Science Foundation of Hubei Province (2016CFB127 and 2016CFB517), Hubei Provincial Department of Education (Q20164505), Shanghai Rising-Star Program (No.16QA1402900), Research Foundation of Hubei Polytechnic University for Talented Scholars (16xjz01R), the National Institutes of Health grants R21 DA042298 (W.L.), R01 GM124152 (W.L.), the National Science Foundation STC award 1231306 (W.L.), and the Flinn Foundation Seed Grant (W.L.).
Li, Duan-Zhuo; Liu, Shun-Fang; Zhu, Lan; Wang, Yu-Xing; Chen, Yi-Xiang; Liu, Jie; Hu, Gang; Yu, Xin; Li, Jian; Zhang, Jin; Wu, Zhi-Xiang; Lu, Han; Liu, Wei; and Liu, Bin, "FBXW8-Dependent Degradation of MRFAP1 in Anaphase Controls Mitotic Cell Death" (2017). Molecular and Cellular Biochemistry Faculty Publications. 124.