Abstract
Although lysine methylation is classically known to regulate histone function, its role in modulating antiviral restriction factor activity remains uncharacterized. Interferon-induced transmembrane protein 3 (IFITM3) was found monomethylated on its lysine 88 residue (IFITM3-K88me1) to reduce its antiviral activity, mediated by the lysine methyltransferase SET7. Vesicular stomatitis virus and influenza A virus infection increased IFITM3-K88me1 levels by promoting the interaction between IFITM3 and SET7, suggesting that this pathway could be hijacked to support infection; conversely, IFN-α reduced IFITM3-K88me1 levels. These findings may have important implications in the design of therapeutics targeting protein methylation against infectious diseases.
Highlights
Interferon-induced transmembrane protein 3 (IFITM3) is a general antiviral host restriction factor against RNA viruses
The interaction between IFITM3 and SET7 was confirmed by reciprocal co-immunoprecipitation using HA-IFITM3 or FLAG-SET7 independently as bait (Fig. 1D) and by in vitro GST pulldown with recombinant GST-IFITM3 and His-SET7 proteins that were purified from E. coli (Fig. 1E)
Other lysine methyltransferases were not screened for their interaction with IFITM3, we believe that the methyltransferase
Summary
IFITM3 is a general antiviral host restriction factor against RNA viruses. Results: SET7-mediated monomethylation of IFITM3 at Lys-88 negatively affected its antiviral activity toward vesicular stomatitis virus (VSV) and influenza A virus (IAV) infection. Lysine methylation is classically known to regulate histone function, its role in modulating antiviral restriction factor activity remains uncharacterized. Vesicular stomatitis virus and influenza A virus infection increased IFITM3-K88me levels by promoting the interaction between IFITM3 and SET7, suggesting that this pathway could be hijacked to support infection; IFN-␣ reduced IFITM3-K88me levels These findings may have important implications in the design of therapeutics targeting protein methylation against infectious diseases. It is appreciated that lysine methylation may affect non-histone proteins, including viral effectors (19 –22), there have yet to be any reports that indicate a role for lysine methylation in controlling the activity of antiviral host restriction factors, and a PTM enzyme has not been identified that targets IFITM3. We focused on uncovering the role of monomethylation on IFITM3 function and finding the PTM enzyme responsible for this process
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