ISG15 deficiency and increased viral resistance in humans but not mice

Nat Commun. 2016 May 19;7:11496. doi: 10.1038/ncomms11496.


ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/β signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism*
  • Female
  • Gene Expression Regulation
  • Humans
  • Interferons / metabolism
  • Mice
  • Primary Cell Culture
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitins / genetics
  • Ubiquitins / immunology
  • Ubiquitins / metabolism*
  • Virus Diseases / immunology*


  • Cytokines
  • G1p2 protein, mouse
  • Ubiquitins
  • ISG15 protein, human
  • Interferons
  • Usp18 protein, mouse
  • Ubiquitin Thiolesterase