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FBXW7-Induced MTOR Degradation Forces Autophagy to Counteract Persistent Prion Infection

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Abstract

Autophagy is an important protein degradation pathway and a part of the innate immune system that is activated in the brain tissue during animal and human prion diseases. However, the possible mechanism by which prion infection triggers autophagy and the significance of activated autophagy on prion accumulation remain unknown. Here, we demonstrated that autophagic flux was enhanced in the persistent prion-infected cell line, SMB-S15. Knockdown of ATG5 and the presence of three autophagic inhibitors resulted in a significant increase of PrPSc. The mammalian target of rapamycin (MTOR) levels in SMB-S15 cells were also markedly decreased, in direct relation to PrPSc accumulation. F-box and WD repeat domain containing 7 (FBXW7) levels in SMB-S15 cells and in the brains of scrapie-agent 263K-infected hamsters were upregulated at the early stage of infection, leading to active ubiquitination and degradation of MTOR. Knockdown of FBXW7 in SMB-S15 cells remarkably inhibited autophagic flux and increased PrPSc accumulation. Thus, we conclude that prion infection induced the expression of FBXW7, which mediated MTOR ubiquitination and degradation, further altering phosphorylation status through cross talk between MTORC1 and AMPK and increasing autophagic flux. Autophagy may serve as innate immunity to degrade PrPSc and maintain prion homeostasis.

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Acknowledgments

This work was supported by Chinese National Natural Science Foundation Grant (81100980, 81101302 and 31100117), China Mega-Project for Infectious Disease (2011ZX10004-101, 2012ZX10004215), and SKLID Development Grant (2012SKLID102, 2011SKLID302, 2011SKLID204, 2011SKLID211).

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Authors and Affiliations

  1. 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

    Yin Xu, Chan Tian, Jing Sun, Jin Zhang, Ke Ren, Xue-Yu Fan, Ke Wang, Hui Wang, Yu-E Yan, Cao Chen, Qi Shi & Xiao-Ping Dong

  2. 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. Yin Xu
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Correspondence to Xiao-Ping Dong.

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Xu, Y., Tian, C., Sun, J. et al. FBXW7-Induced MTOR Degradation Forces Autophagy to Counteract Persistent Prion Infection. Mol Neurobiol 53, 706–719 (2016). https://doi.org/10.1007/s12035-014-9028-7

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