Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
Xianqin Zhang
(1)
,
Bo Bogunovic
,
Béatrice Payelle-Brogard
(2)
,
Véronique François-Newton
(2)
,
Scott Speer
,
Chao Yuan
,
Stefano Volpi
(3)
,
Zhi Li
(2)
,
Ozden Sanal
(4)
,
Ilhan Tezcan
(4)
,
Gillian Rice
(5)
,
Chunyuan Chen
,
Nahal Mansouri
(6)
,
Seyed Alireza Mahdaviani
(7)
,
Yuval Itan
(8)
,
Bertrand Boisson
(9)
,
Satoshi Okada
(8)
,
Lu Zeng
,
Xing Wang
,
Hui Jiang
(10)
,
Wenqiang Liu
,
Tiantian Han
,
Delin Liu
,
Tao Ma
,
Bo Wang
(11)
,
Mugen Liu
(1)
,
Jing-Yu Liu
,
Qing Wang
(12)
,
Dilek Yalnizoglu
,
Lilliana Radoshevich
(13)
,
Gilles Uze
(14)
,
Philippe Gros
(15)
,
Flore Rozenberg
(16)
,
Shen-Ying Zhang
(8)
,
Emmanuelle Jouanguy
(17)
,
Jacinta Bustamante
(18)
,
Adolfo García-Sastre
(19)
,
Laurent Abel
(17)
,
Pierre Lebon
(20)
,
Luigi Notarangelo
(21)
,
Yanick Crow
(18)
,
Stephanie Boisson-Dupuis
(18)
,
Jean-Laurent Casanova
(17)
,
Sandra Pellegrini
(2)
1
HUST -
Huazhong University of Science and Technology [Wuhan]
2 Signalisation des Cytokines
3 Istituto Giannina Gaslini, Genova
4 Ankara University School of Medicine [Turkey]
5 University of Manchester [Manchester]
6 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
7 Shahid Beheshti University
8 St. Giles Laboratory of Human Genetics of Infectious Diseases
9 ISV - Institut des sciences du végétal
10 Department of Mathematics [Nanjing]
11 IRCOM - Institut de Recherche en Communications Optiques et Microondes
12 Hunan Institute of Science and Technology
13 UIBC - Interactions Bactéries-Cellules
14 DIMNP - Dynamique des interactions membranaires normales et pathologiques
15 DPhP - Département de Physique des Particules (ex SPP)
16 Laboratoire de Virologie
17 Inserm U980 - Génétique Humaine des Maladies Infectieuses
18 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
19 MSSM - Icahn School of Medicine at Mount Sinai [New York]
20 Service de virologie
21 UniBs - Università degli Studi di Brescia = University of Brescia
2 Signalisation des Cytokines
3 Istituto Giannina Gaslini, Genova
4 Ankara University School of Medicine [Turkey]
5 University of Manchester [Manchester]
6 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
7 Shahid Beheshti University
8 St. Giles Laboratory of Human Genetics of Infectious Diseases
9 ISV - Institut des sciences du végétal
10 Department of Mathematics [Nanjing]
11 IRCOM - Institut de Recherche en Communications Optiques et Microondes
12 Hunan Institute of Science and Technology
13 UIBC - Interactions Bactéries-Cellules
14 DIMNP - Dynamique des interactions membranaires normales et pathologiques
15 DPhP - Département de Physique des Particules (ex SPP)
16 Laboratoire de Virologie
17 Inserm U980 - Génétique Humaine des Maladies Infectieuses
18 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
19 MSSM - Icahn School of Medicine at Mount Sinai [New York]
20 Service de virologie
21 UniBs - Università degli Studi di Brescia = University of Brescia
Bo Bogunovic
- Function : Author
Scott Speer
- Function : Author
Chao Yuan
- Function : Author
Stefano Volpi
- Function : Author
- PersonId : 791249
- ORCID : 0000-0002-7129-868X
Zhi Li
- Function : Author
- PersonId : 173493
- IdHAL : zhi-li
- ORCID : 0000-0003-4422-4914
- IdRef : 225663031
Chunyuan Chen
- Function : Author
Seyed Alireza Mahdaviani
- Function : Author
- PersonId : 779164
- ORCID : 0000-0001-6224-4797
Yuval Itan
- Function : Author
- PersonId : 955126
Bertrand Boisson
- Function : Author
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- IdRef : 08188317X
Satoshi Okada
- Function : Author
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- ORCID : 0000-0002-4622-5657
Lu Zeng
- Function : Author
Xing Wang
- Function : Author
Wenqiang Liu
- Function : Author
Tiantian Han
- Function : Author
Delin Liu
- Function : Author
Tao Ma
- Function : Author
Bo Wang
- Function : Author
- PersonId : 761439
- ORCID : 0000-0002-5579-6830
Jing-Yu Liu
- Function : Author
Dilek Yalnizoglu
- Function : Author
Philippe Gros
- Function : Author
- PersonId : 18464
- IdHAL : philippe-c-gros
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- IdRef : 121657094
Flore Rozenberg
- Function : Author
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- ORCID : 0000-0003-0991-7774
- IdRef : 089425561
Shen-Ying Zhang
- Function : Author
- PersonId : 955133
Emmanuelle Jouanguy
- Function : Author
- PersonId : 756190
- ORCID : 0000-0002-7358-9157
- IdRef : 224367455
Jacinta Bustamante
- Function : Author
- PersonId : 757899
- ORCID : 0000-0002-3439-2482
- IdRef : 124593461
Laurent Abel
- Function : Author
- PersonId : 756191
- ORCID : 0000-0001-7016-6493
- IdRef : 07779432X
Luigi Notarangelo
- Function : Author
- PersonId : 758298
- ORCID : 0000-0002-8335-0262
Yanick Crow
- Function : Author
- PersonId : 11918
- IdHAL : yanick-crow
- ORCID : 0000-0001-7211-7564
- IdRef : 227205359
Jean-Laurent Casanova
- Function : Author
- PersonId : 756193
- ORCID : 0000-0002-7782-4169
- IdRef : 073388726
Sandra Pellegrini
- Function : Author
- PersonId : 758265
- ORCID : 0000-0001-5837-7589
- IdRef : 124575269
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.