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

PLoS Pathog. 2017 Dec 27;13(12):e1006773. doi: 10.1371/journal.ppat.1006773. eCollection 2017 Dec.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Female
  • HEK293 Cells
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Influenza A virus / pathogenicity*
  • Influenza A virus / physiology
  • Membrane Proteins / chemistry
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Methylation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Models, Biological
  • Orthomyxoviridae Infections / etiology
  • Orthomyxoviridae Infections / metabolism
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*
  • Tranylcypromine / pharmacology
  • Vesicular stomatitis Indiana virus / pathogenicity
  • Vesicular stomatitis Indiana virus / physiology
  • Virus Replication
  • Zika Virus / pathogenicity
  • Zika Virus / physiology

Substances

  • Enzyme Inhibitors
  • IFITM3 protein, human
  • Membrane Proteins
  • RNA-Binding Proteins
  • fragilis protein, mouse
  • Tranylcypromine
  • Histone Demethylases
  • KDM1a protein, mouse
  • KDM1A protein, human

Grants and funding

Our research is supported by National Science Foundation for Distinguished Young Scholars(http://www.nsfc.gov.cn/publish/portal1/tab158/info39460.htm) 31525008; National Natural Science Foundation of China (http://www.nsfc.gov.cn/publish/portal1/tab158/info39460.htm); 81590766, 81330072, 81360250, 31500714, 31370863, 81772202, 31570171; Chinese National Program on Key Basic Research Project Grants (http://www.most.gov.cn/eng/programmes1/200610/t20061009_36223.htm) 2014CB541803 and 2014CB541903; The National Key Research and Development Program of China (http://www.most.gov.cn/eng/) 2016YFC1200403; Shanghai Academic Research Leader (http://www.stcsm.gov.cn/english/) 16XD1403800; “Rising Star Talent Program” from the Science and Technology Commission of Shanghai Municipality (http://www.stcsm.gov.cn/english/) 15QA1404000 and the Youth Innovation Promotion Association CAS (http://www.yicas.cn/), and the 100 Talent from CAS (http://www.cas.ac.cn/) and 1000 Talent from Science and Technology Commission of Shanghai Municipality to DL (http://www.1000plan.org/qrjh/section/2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.