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

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.

IFITM Genes, Variants, and Their Roles in the Control and Pathogenesis of Viral Infections

“…Importantly, ubiquitination and endocytosis of IFITM3 is required for mTOR inhibitor-induced degradation of IFITM3 (Shi et al, 2018). In addition, IFITM3 K88 can be monomethylated by lysine methyltransferase SET7 and demethylated by histone demethylase LSD1 (Shan et al, 2013, 2017). While vesicular stomatitis virus (VSV) and IAV infection increased IFITM3-K88me1 levels by promoting the interaction between IFITM3 and SET7 and disassociation from LSD1 to attenuate IFITM3 antiviral activity, IFN-α reduced IFITM3-K88me1 levels and increased its antiviral activity (Shan et al, 2013, 2017).…”

The Catalytic-Dependent and -Independent Roles of Lsd1 and Lsd2 Lysine Demethylases in Heterochromatin Formation in Schizosaccharomyces pombe

“…While functions of Lsd proteins beyond histone demethylation have not been well-demonstrated in S. pombe, non-histone substrates have been described for human LSD1 and LSD2. For instance, LSD1 demethylates p53 to inhibit apoptosis [82], targets IFITM3 (interferon-inducible transmembrane family protein 3) to restrict influenza A virus infection in response to IFNα [83], and has been shown to activate HIV transcription through the demethylation of the HIV Tat protein [84]. LSD2 has been found to target non-histone substrates as well, promoting the degradation of OGT (O-GlcNAc transferase) through unexpected E3 ubiquitin ligase activity, unrelated to its amine oxidase function [85].…”

Antiviral Protection by IFITM3 In Vivo

“…(2) Monomethylation of IFITM3 at K88 by the SET7 methyltransferase decreases its antiviral activity [ 26 ]. This methylation can also be removed by the histone demethylase LSD1, which is recruited to IFITM3 during IFN treatment of cells [ 27 ]. Additional studies will be required to determine the molecular mechanism by which K88 methylation inhibits IFITM3 and whether this inhibition is beneficial to cells.…”