The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry

Nat Microbiol. 2018 Dec;3(12):1369-1376. doi: 10.1038/s41564-018-0273-9. Epub 2018 Nov 26.


Interferons (IFNs) mediate cellular defence against viral pathogens by upregulation of IFN-stimulated genes whose products interact with viral components or alter cellular physiology to suppress viral replication1-3. Among the IFN-stimulated genes that can inhibit influenza A virus (IAV)4 are the myxovirus resistance 1 GTPase5 and IFN-induced transmembrane protein 3 (refs 6,7). Here, we use ectopic expression and gene knockout to demonstrate that the IFN-inducible 219-amino acid short isoform of human nuclear receptor coactivator 7 (NCOA7) is an inhibitor of IAV as well as other viruses that enter the cell by endocytosis, including hepatitis C virus. NCOA7 interacts with the vacuolar H+-ATPase (V-ATPase) and its expression promotes cytoplasmic vesicle acidification, lysosomal protease activity and the degradation of endocytosed antigen. Step-wise dissection of the IAV entry pathway demonstrates that NCOA7 inhibits fusion of the viral and endosomal membranes and subsequent nuclear translocation of viral ribonucleoproteins. Therefore, NCOA7 provides a mechanism for immune regulation of endolysosomal physiology that not only suppresses viral entry into the cytosol from this compartment but may also regulate other V-ATPase-associated cellular processes, such as physiological adjustments to nutritional status, or the maturation and function of antigen-presenting cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Cell Line
  • Endosomes / drug effects*
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Influenza A virus / physiology
  • Interferons / metabolism*
  • Lysosomes / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nuclear Receptor Coactivators / antagonists & inhibitors*
  • Nuclear Receptor Coactivators / genetics
  • Nuclear Receptor Coactivators / immunology
  • Nuclear Receptor Coactivators / metabolism*
  • Protein Isoforms
  • Proteolysis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Vacuolar Proton-Translocating ATPases
  • Virus Internalization / drug effects*


  • IFITM3 protein, human
  • Membrane Proteins
  • NCOA7 protein, human
  • Nuclear Receptor Coactivators
  • Protein Isoforms
  • RNA-Binding Proteins
  • Interferons
  • Vacuolar Proton-Translocating ATPases