Abstract
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.
Highlights
The specific, rapid, and temporally controlled proteolysis of cellular regulators by the ubiquitinproteasome system (UPS) determined the unidirectional progression through the cell cycle [1]
MRFAP1 was detected in the final elution of Flag-FBXW8 group and flow through of both groups (Figure 1A), suggesting that at least one part of endogenous MRFAP1 was associated with FBXW8
Previous studies showed that substrates of Cullin-Ring Ligases (CRL) were highly accumulated upon MLN4924 administration, giving the possibility to identify the substrates of CRLs by Mass Spectrum (MS) [13,14,15]
Summary
The specific, rapid, and temporally controlled proteolysis of cellular regulators by the ubiquitinproteasome system (UPS) determined the unidirectional progression through the cell cycle [1] The specificity of this system is mainly determined by E3 ubiquitin ligases [2]. The human genome encodes more than 70 F-box proteins that contain a homologous 40-amino-acid F-box domain which can be further divided into three major classes: the FBXW family, the FBXL family, and the FBXO family [5]. Among these F-box proteins, FBXW8 is the receptor component of an SCF complex, and the unique F-box protein known to interact with Cul7 [6]. Cul7/ FBXW8 ubiquitin ligase-mediated HPK1 (hematopoietic progenitor kinase-1) degradation played a critical role in cell proliferation and differentiation [8]
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