Human Papillomavirus 16 oncoprotein E7 retards mitotic progression by blocking Mps1-MAP4 signaling cascade

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Abstract

Human epithelial cells can be infected by more than 200 types of human papilloma viruses (HPVs), and persistent HPV infections lead to cervical cancer or other deadly cancers. It has been established that mitotic progression is critical for HPV16 infection, but the underlying mechanism remains unknown. Here, we report that oncoprotein E7 of HPV16 but not HPV18 retards mitotic progression in host cell by direct binding to the C terminus of Microtubule-Associated Protein 4 (MAP4). MAP4 is a novel bona fide target of HPV16E7 protein which binds and recruits the latter to spindle microtubule in mitosis. HPV16E7 protein promotes MAP4 stability by inhibiting MAP4 phosphorylation- mediated degradation to increase the stability of microtubule polymerization and cause an extend mitotic progression. We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation. Mutations of MAP4 at T927ES928E partially abolished E7-binding capacity and rescued mitotic progression in host cells. In conclusion, our study reveals a molecular mechanism by which HPV16E7 perturbs host mitotic progression by interfering Mps1-MAP4 signaling cascade, which results in an extended infection window and may facilitate the persistent HPV16 infection.

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Acknowledgements

This work was supported in part by grants from National Basic Research Program of China (2014CB138505) and National Natural Science Foundation of China (81871130).

Author information

Y.G. and X.Z. performed the majority of experiments, analyzed the data, and prepared the figures. Q.X. performed the live-cell imaging experiment. F.N., W.Z., and J.L. assisted in the experiments and data analysis. F.G. and X.S. performed histological analysis. C.L., R.H., and J.T. constructed the plasmids. R.L., L.Z., and L.C. performed manuscript proofreading. R.Z.M. directed the project. Y.G., X.Z., and R.Z.M wrote the paper.

Correspondence to Runlin Z. Ma.

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Guo, Y., Zhang, X., Xu, Q. et al. Human Papillomavirus 16 oncoprotein E7 retards mitotic progression by blocking Mps1-MAP4 signaling cascade. Oncogene 38, 5959–5970 (2019) doi:10.1038/s41388-019-0851-1

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