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The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization

Rui Jia1, Qinghua Pan, Shilei Ding

  • 1Key Laboratory of Molecular Microbiology and Biotechnology (Ministry of Education) and Key Laboratory of Microbial Functional Genomics (Tianjin), College of Life Sciences, Nankai University, Tianjin, China.

Journal of Virology
|October 12, 2012
PubMed

Insights

Interferon-inducible transmembrane protein 3 (IFITM3) variants affect viral restriction. A specific IFITM3 variant lacking N-terminal amino acids impairs influenza A virus inhibition by altering protein localization, but not HIV-1 inhibition.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Interferon-inducible transmembrane (IFITM) proteins restrict enveloped virus infections.
  • A specific IFITM3 allele, lacking the N-terminal 21 amino acids, is associated with severe flu outcomes and fails to inhibit influenza A virus.
  • Viral entry mechanisms, including pH-dependent and independent pathways, influence susceptibility to IFITM-mediated restriction.

Purpose of the Study:

  • To investigate the functional role of the N-terminal 21 amino acids of IFITM3 in viral restriction.
  • To determine how the deletion of the N-terminal region affects IFITM3 localization and its ability to inhibit different viruses.
  • To elucidate the mechanism by which IFITM3 restricts pH-dependent and pH-independent viral entry.

Main Methods:

  • Site-directed mutagenesis to create an IFITM3 mutant lacking the N-terminal 21 amino acids.
  • Confocal microscopy to assess the subcellular localization of wild-type and mutant IFITM3.
  • Viral infection assays using influenza A virus and HIV-1 to evaluate antiviral activity.

Main Results:

  • Deletion of the N-terminal 21 amino acids of IFITM3 caused its relocation from endosomal compartments to the cell periphery.
  • The N-terminal deletion mutant lost the ability to inhibit influenza A virus, which enters cells via low pH-dependent endosomes.
  • Both wild-type IFITM3 and the N-terminal deletion mutant exhibited equal efficacy in inhibiting HIV-1 replication, which enters cells via a pH-independent route.

Conclusions:

  • The N-terminal region of IFITM3 is specifically required for restricting viruses that utilize pH-dependent entry pathways, such as influenza A virus.
  • IFITM3 can inhibit viruses employing diverse entry mechanisms, with its N-terminal domain playing a critical role in targeting specific routes.
  • Understanding IFITM3's differential activity based on viral entry mechanisms provides insights into host antiviral defense strategies.

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