Open AccessHistone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation
Author(s) -
Jiaoyu Shan,
Binbin Zhao,
Shuyuan Zhao,
Jia Nie,
Rong Deng,
Rui Xiong,
Andy Tsun,
Weiqi Pan,
Hanzhi Zhao,
Ling Chen,
Ying Jin,
Qian Zhou,
Kawing Lui,
Rui Li,
Dan Li,
Bing Sun,
Dimitri Lavillette,
Ke Xu,
Bin Li
Publication year - 2017
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006773
Subject(s) - biology , demethylase , virology , virus , rna , histone , rna virus , influenza a virus , viral replication , vesicular stomatitis virus , chromatin , dna , gene , genetics
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.