Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation

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Zhang X., Bogunovic D., Payelle-Brogard B., Francois-Newton V., Speer S. D., Yuan C., ...More

NATURE, vol.517, no.7532, pp.89-103, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 517 Issue: 7532
  • Publication Date: 2015
  • Doi Number: 10.1038/nature13801
  • Journal Name: NATURE
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.89-103
  • Hacettepe University Affiliated: Yes


Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice(1-4). We previously published a study describing humans with inherited ISG15deficiency but without unusually severe viral diseases(5). We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia(6-9). We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18(10,11), a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.