Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation - Institut Pasteur Access content directly
Journal Articles Nature Year : 2015

Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation

Bo Bogunovic
  • Function : Author
Béatrice Payelle-Brogard
  • Function : Author
  • PersonId : 841261
Scott Speer
  • Function : Author
Chao Yuan
  • Function : Author
Stefano Volpi
Zhi Li
Gillian Rice
  • Function : Author
  • PersonId : 932509
Chunyuan Chen
  • Function : Author
Seyed Alireza Mahdaviani
Bertrand Boisson
Lu Zeng
  • Function : Author
Xing Wang
  • Function : Author
Hui Jiang
  • Function : Author
  • PersonId : 988798
Wenqiang Liu
  • Function : Author
Tiantian Han
  • Function : Author
Delin Liu
  • Function : Author
Tao Ma
  • Function : Author
Jing-Yu Liu
  • Function : Author
Dilek Yalnizoglu
  • Function : Author
Lilliana Radoshevich
  • Function : Author
  • PersonId : 969036
Flore Rozenberg
Laurent Abel
Yanick Crow
Sandra Pellegrini


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

Dates and versions

pasteur-02070691 , version 1 (18-03-2019)



Xianqin Zhang, Bo Bogunovic, Béatrice Payelle-Brogard, Véronique François-Newton, Scott Speer, et al.. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature, 2015, 517 (7532), pp.89-93. ⟨10.1038/nature13801⟩. ⟨pasteur-02070691⟩
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