Viral-Mediated AURKB Cleavage Promotes Cell Segregation and Tumorigenesis

Qing Zhu,Ling Ding,Zhenguo Zi,Shujun Gao,Chong Wang,Yuyan Wang,Caixia Zhu,Zhenghong Yuan,Fang Wei,Qiliang Cai

doi:10.1016/j.celrep.2019.02.106

Qing Zhu, Ling Ding + Show 8 more

Open Access

https://doi.org/10.1016/j.celrep.2019.02.106

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Abstract

Aurora kinase B (AURKB), a central regulator of chromosome segregation and cytokinesis, is aberrantly expressed in various cancer cells. However, the relationship of AURKB and oncogenic viruses in cancer progression remains unclear. Here, we reveal that N-cleaved isoforms of AURKB exist in several oncovirus-associatedtumor cells and patient cancer tissues, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV), and human papillomavirus virus (HPV). Mechanistically, in KSHV-infected tumor cells, the latent viral antigen LANA cleaves AURKB at Asp76 in a serine protease-dependent manner. The N'-AURKB relocalizes to thespindle pole and promotes the metaphase-to-telophase transition in mitotic cells. Introduction of N'-AURKB but not C'-AURKB promotes colony formation and malignant growth of tumor cells invitro and invivo using a murine xenograft model. Altogether, our findings uncover a proteolytic cleavage mechanism by which oncoviruses induce cancer cell segregation and tumorigenesis.

Highlights

Mitosis is a dynamic and complex process, and the precise control of mitotic regulators is indispensable (Carmena and Earnshaw, 2003; Fu et al, 2007; Gully et al, 2012)
We show that the cleavage of Aurora kinase B (AURKB) at the N terminus occurs in the Kaposi’s sarcoma-associated herpesvirus (KSHV) latently infected tumor cells, which is induced by LANA or KSHV de novo infection in a serine protease-dependent manner
Because the antibodies against AURKA or AURKB target the myc epitope located at the C terminus of the proteins, the $35-kDa band may be a short form of the AURKA or AURKB protein, with its N terminus deleted

Summary

Introduction

Mitosis is a dynamic and complex process, and the precise control of mitotic regulators is indispensable (Carmena and Earnshaw, 2003; Fu et al, 2007; Gully et al, 2012). Reports have revealed that a single amino acid mutant involving G198N converts AURKA into a AURKB-like kinase, which compensates for the loss of AURKB during chromosome misalignment and premature exit of cells from mitosis (Fu et al, 2009). These findings suggest the existence of a compensatory mechanism to rescue the loss of each kinase in mammalian cells

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