FBXW8-dependent degradation of MRFAP1 in anaphase controls mitotic cell death
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Duan-Zhuo Li1,*, Shun-Fang Liu2,*, Lan Zhu3,*, Yu-Xing Wang1, Yi-Xiang Chen1, Jie Liu1, Gang Hu1, Xin Yu1, Jian Li4, Jin Zhang5, Zhi-Xiang Wu6, Han Lu7, Wei Liu3 and Bin Liu1
1Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Central Hospital of Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, Hubei 435003, PR China
2Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China
3School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
4Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
5School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330031, PR China
6Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai 200092, PR China
7Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai 200025, PR China
*These authors contributed equally to this work
Wei Liu, email: [email protected]
Bin Liu, email: [email protected]
Keywords: FBXW8, genomic instability, MRFAP1, mitosis
Received: May 24, 2017 Accepted: September 24, 2017 Published: October 12, 2017
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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