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Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy

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Abstract

Polo-like kinase 3 (PLK3) is the main cause of cell cycle reentry-related neuronal apoptosis which has been implicated in the pathogenesis of prion diseases. Previous work also showed the regulatory activity of exogenous PLK3 on the degradation of PrP (prion protein) mutants and pathogenic PrPSc; however, the precise mechanisms remain unknown. In this study, we identified that the overexpression of PLK3-mediated degradation of PrP mutant and PrPSc was repressed by lysosome rather than by proteasomal and macroautophagy inhibitors. Core components of chaperone-mediated autophagy (CMA) effectors, lysosome-associated membrane protein type 2A (LAMP2a), and heat shock cognate protein 70 (Hsc70) are markedly decreased in the HEK293T cells expressing PrP mutant and scrapie-infected cell line SMB-S15. Meanwhile, PrP mutant showed ability to interact with LAMP2a and Hsc70. Overexpression of PLK3 sufficiently increased the cellular levels of LAMP2a and Hsc70, accompanying with declining the accumulations of PrP mutant and PrPSc. The kinase domain (KD) of PLK3 was responsible for elevating LAMP2a and Hsc70. Knockdown of endogenous PLK3 enhanced the activity of macroautophagy in the cultured cells. Moreover, time-dependent reductions of LAMP2a and Hsc70 were also observed in the brain tissues of hamster-adapted scrapie agent 263K-infected hamsters, indicating an impairment of CMA during prion infection. Those data indicate that the overexpression of PLK3-mediated degradation of abnormal PrP is largely dependent on CMA pathway.

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Acknowledgments

This work was supported by SKLID Development Grant (2014SKLID201), Chinese National Natural Science Foundation Grant (81472004, 31270185, 81101302, 81273202), Clinical Medicine Science and Technology Project of Jiangsu province of China (BL2013024), Program of Innovative Research Team of Jiangsu Province, Construct Program of the Advanced Disciplines and the Key Discipline in Universities of Jiangsu Province and Construct Program of the Key Discipline of Jiangsu University. The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Immunology and Key Laboratory of Laboratory Medicine of Jiangsu Province, Medical School, Jiangsu University, Zhenjiang, 212013, Jiangsu, China

    Hui Wang & Qi-Xiang Shao

  2. State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing, 102206, China

    Hui Wang, Chan Tian, Jing Sun, Li-Na Chen, Yan Lv, Xiao-Dong Yang, Kang Xiao, Jing Wang, Cao Chen, Qi Shi & Xiao-Ping Dong

  3. Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China

    Xiao-Ping Dong

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  1. Hui Wang
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Correspondence to Qi-Xiang Shao or Xiao-Ping Dong.

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Wang, H., Tian, C., Sun, J. et al. Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy. Mol Neurobiol 54, 4401–4413 (2017). https://doi.org/10.1007/s12035-016-9985-0

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