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- DOI: 10.1038/nature13801
- PMID: 25307056
- UKPMCID: 25307056
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Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.
Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, Béatrice; Francois-Newton, Véronique; Speer, Scott D; Yuan, Chao; Volpi, Stefano; Li, Zhi; Sanal, Ozden; Mansouri, Davood; Tezcan, Ilhan; Rice, Gillian I; Chen, Chunyuan; Mansouri, Nahal; Mahdaviani, Seyed Alireza; Itan, Yuval; Boisson, Bertrand; Okada, Satoshi; Zeng, Lu; Wang, Xing; Jiang, Hui; Liu, Wenqiang; Han, Tiantian; Liu, Delin; Ma, Tao; Wang, Bo; Liu, Mugen; Liu, Jing-Yu; Wang, Qing K; Yalnizoglu, Dilek; Radoshevich, Lilliana; Uzé, Gilles; Gros, Philippe; Rozenberg, Flore; Zhang, Shen-Ying; Jouanguy, Emmanuelle; Bustamante, Jacinta; GarcÃa-Sastre, Adolfo; Abel, Laurent; Lebon, Pierre; Notarangelo, Luigi D; Crow, Yanick J; Boisson-Dupuis, Stéphanie; Casanova, Jean-Laurent; Pellegrini, Sandra
Nature. 2015;517(7532):89-93.
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Full-text held externally
- DOI: 10.1038/nature13801
- PMID: 25307056
- UKPMCID: 25307056
Abstract
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.
Bibliographic metadata
- Zhang, Xianqin
- Bogunovic, Dusan
- Payelle-Brogard, Béatrice
- Francois-Newton, Véronique
- Speer, Scott D
- Yuan, Chao
- Volpi, Stefano
- Li, Zhi
- Sanal, Ozden
- Mansouri, Davood
- Tezcan, Ilhan
- Rice, Gillian I
- Chen, Chunyuan
- Mansouri, Nahal
- Mahdaviani, Seyed Alireza
- Itan, Yuval
- Boisson, Bertrand
- Okada, Satoshi
- Zeng, Lu
- Wang, Xing
- Jiang, Hui
- Liu, Wenqiang
- Han, Tiantian
- Liu, Delin
- Ma, Tao
- Wang, Bo
- Liu, Mugen
- Liu, Jing-Yu
- Wang, Qing K
- Yalnizoglu, Dilek
- Radoshevich, Lilliana
- Uzé, Gilles
- Gros, Philippe
- Rozenberg, Flore
- Zhang, Shen-Ying
- Jouanguy, Emmanuelle
- Bustamante, Jacinta
- GarcÃa-Sastre, Adolfo
- Abel, Laurent
- Lebon, Pierre
- Notarangelo, Luigi D
- Crow, Yanick J
- Boisson-Dupuis, Stéphanie
- Casanova, Jean-Laurent
- Pellegrini, Sandra