Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation

PLoS Pathogens

Rong Deng¹  Bin Li¹  Bing Sun²  Weiqi Pan²  Andy Tsun²  Ling Chen²  Dimitri Lavillette²  Jiaoyu Shan²  Rui Xiong²  Zhao Shan²  Zhikang Qian⁴  Rui Liang⁴  Dan Li⁵  Hanzhi Zhao⁶  Kawing Lui⁷  Ying Jin⁷  Binbin Zhao⁸  Jia Nie⁹  Ke Xu⁹ 

[1] Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai JiaoTong University, Shanghai, China;CAS Center for Excellence in Molecular Cell Science, CAS Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;CAS Center for Excellence in Molecular Cell Science, CAS Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Virology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;CAS Center for Excellence in Molecular Cell Science, Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai, China;CAS Key Laboratory of Molecular Virology and Immunology, Unit of Herpesvirus and Molecular Virology Research, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;CAS Key Laboratory of Molecular Virology and Immunology, Unit of interspecies transmission of arboviruses and therapeutics research, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China;Human Parasitology Department of Basic Medicine College, Xinjiang Medical University, Urumqi, China;Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China

关键词: Vesicular stomatitis virus;    RNA viruses;    Methylation;    Zika virus;    Influenza A virus;    Immunoprecipitation;    Viral replication;    DNA replication;   

DOI  :  10.1371/journal.ppat.1006773

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The histone demethylase LSD1 has been known as a key transcriptional coactivator for DNA viruses such as herpes virus. Inhibition of LSD1 was found to block viral genome transcription and lytic replication of DNA viruses. However, RNA virus genomes do not rely on chromatin structure and histone association, and the role of demethylase activity of LSD1 in RNA virus infections is not anticipated. Here, we identify that, contrary to its role in enhancing DNA virus replication, LSD1 limits RNA virus replication by demethylating and activating IFITM3 which is a host restriction factor for many RNA viruses. We have found that LSD1 is recruited to demethylate IFITM3 at position K88 under IFNα treatment. However, infection by either Vesicular Stomatitis Virus (VSV) or Influenza A Virus (IAV) triggers methylation of IFITM3 by promoting its disassociation from LSD1. Accordingly, inhibition of the enzymatic activity of LSD1 by Trans-2-phenylcyclopropylamine hydrochloride (TCP) increases IFITM3 monomethylation which leads to more severe disease outcomes in IAV-infected mice. In summary, our findings highlight the opposite role of LSD1 in fighting RNA viruses comparing to DNA viruses infection. Our data suggest that the demethylation of IFITM3 by LSD1 is beneficial for the host to fight against RNA virus infection.

【 授权许可】

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