ISG15 deficiency and increased viral resistance in humans but not mice


Speer S. D. , Li Z., Buta S., Payelle-Brogard B., Qian L., Vigant F., ...Daha Fazla

NATURE COMMUNICATIONS, cilt.7, 2016 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 7
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1038/ncomms11496
  • Dergi Adı: NATURE COMMUNICATIONS

Özet

ISG15 is an interferon (IFN)-alpha/beta-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-gamma-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-alpha/beta 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.