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Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain

Camilla To Benfield1, Farrell MacKenzie2, Markus Ritzefeld3

  • 1Department of Pathobiology and Population Sciences, Royal Veterinary College, University of London, London, UK cbenfield@rvc.ac.uk.

Life Science Alliance
|December 13, 2019
PubMed

Insights

Bat interferon-induced transmembrane proteins (IFITMs) show adaptive evolution. S-palmitoylation of microbat IFITM3 on specific cysteines is critical for restricting endosomally-entering viruses, revealing a key functional determinant.

Area of Science:

  • Virology
  • Cell Biology
  • Evolutionary Biology

Background:

  • Host interferon-induced transmembrane proteins (IFITMs) act as broad-spectrum antiviral factors.
  • IFITM3 specifically restricts viruses entering cells via acidic endosomes, many originating from bats.
  • Previous work showed microbat IFITM3 possesses antiviral properties.

Purpose of the Study:

  • To investigate adaptive evolution in bat IFITMs.
  • To identify functionally important sites within bat IFITMs, particularly related to antiviral activity.
  • To elucidate the role of S-palmitoylation in Chiropteran IFITM3 function.

Main Methods:

  • Comparative analysis of bat IFITM sequences to identify adaptive evolution.
  • Site-directed mutagenesis of microbat IFITM3 at codon 70 and conserved cysteine residues (C71, C72, C105).
  • Assessment of viral restriction activity, subcellular localization, and S-palmitoylation status of wild-type and mutant IFITM3 proteins.

Main Results:

  • Bat IFITMs exhibit significant adaptive evolution, with high variability at codon 70 within the CD225 domain.
  • Mutation at codon 70 in microbat IFITM3 impairs restriction of viruses entering via endosomes, altering localization and reducing S-palmitoylation.
  • Microbat IFITM3 is S-palmitoylated on C71, C72, and C105; mutations at these sites abolish antiviral activity and cause relocalization to Golgi-associated sites.

Conclusions:

  • S-palmitoylation is essential for the antiviral function of Chiropteran IFITM3.
  • Specific cysteine residues (C71, C72, C105) and the variable site at codon 70 are key determinants of IFITM3 S-palmitoylation and antiviral activity.
  • Understanding these molecular mechanisms provides insight into host-pathogen interactions involving bat-borne viruses.

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