The E3 ligase subunit FBXO45 binds the interferon-λ receptor and promotes its degradation during influenza virus infection

J Biol Chem. 2022 Dec;298(12):102698. doi: 10.1016/j.jbc.2022.102698. Epub 2022 Nov 13.

Abstract

Influenza remains a major public health challenge, as the viral infection activates multiple biological networks linked to altered host innate immunity. Following infection, IFN-λ, a ligand crucial for the resolution of viral infections, is known to bind to its cognate receptor, IFNLR1, in lung epithelia. However, little is known regarding the molecular expression and regulation of IFNLR1. Here, we show that IFNLR1 is a labile protein in human airway epithelia that is rapidly degraded after influenza infection. Using an unbiased proximal ligation biotin screen, we first identified that the Skp-Cullin-F box E3 ligase subunit, FBXO45, binds to IFNLR1. We demonstrate that FBXO45, induced in response to influenza infection, mediates IFNLR1 protein polyubiquitination and degradation through the ubiquitin-proteasome system by docking with its intracellular receptor domain. Furthermore, we found ectopically expressed FBXO45 and its silencing in cells differentially regulated both IFNLR1 protein stability and interferon-stimulated gene expression. Mutagenesis studies also indicated that expression of a K319R/K320R IFNLR1 variant in cells exhibited reduced polyubiquitination, yet greater stability and proteolytic resistance to FBXO45 and influenza-mediated receptor degradation. These results indicate that the IFN-λ-IFNLR1 receptor axis is tightly regulated by the Skp-Cullin-F box ubiquitin machinery, a pathway that may be exploited by influenza infection as a means to limit antiviral responses.

Keywords: E3 ubiquitin ligase; F-box protein; IFNLR1; influenza; interferon; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cullin Proteins / immunology
  • Humans
  • Influenza, Human* / immunology
  • Interferon Lambda
  • Interferons / immunology
  • Protein Binding
  • Receptors, Interferon / immunology
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Cullin Proteins
  • FBXO45 protein, human
  • Interferon Lambda
  • Interferons
  • Receptors, Interferon
  • Ubiquitin
  • Ubiquitin-Protein Ligases