The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Similarly, ISG15, an interferon-inducible protein necessary for viral protection in mice, does not have the same critical role in humans(48-50).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [49]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Soluble TRAIL activates cell death pathways in hepatocytes in response to ethanol consumption and has been implicated in hepatic steatosis and hepatocyte death in ASH (49).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [49]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Baechler, E. C., Batliwalla, F., Karypis, G., Gaffney, P. M., Ortmann, W. A., Espe, K. J., Shark, K. B., Grande, W. J., Hughes, K. M. H., Kapur, V., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0337679100 · Cited by 2,246
Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus Blood
Bennett, L. B., Palucka, K., Arce, E., Cantrell, V., Borvák, J., Banchereau, J., & Pascual, V. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021553 · Cited by 1,990
Genetic Dissection of Immunity to Mycobacteria: The Human Model
Casanova, J., & Abel, L. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.081501.125851 · Cited by 1,006
Self-citationDeregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer
Frescas, D., & Pagano, M. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2396 · Cited by 903
Mycobacterial Disease and Impaired IFN-γ Immunity in Humans with Inherited ISG15 Deficiency
Bogunovic, D., Byun, M., Durfee, L. A., Abhyankar, A., Sanal, O., Mansouri, D., Salem, S., Radovanovic, I., Grant, A. V., Adimi, P., et al. (2012) · Science · doi:10.1126/science.1224026 · Cited by 572
Self-citationRice, G., Forte, G. M. A., Szynkiewicz, M., Chase, D. S., Aeby, A., Abdel‐Hamid, M. S., Ackroyd, S., Allcock, R., Bailey, K. M., Balottin, U., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70258-8 · Cited by 444
Self-citationUBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity
Malakhova, O. A., Kim, K. I. I., Luo, J.-K., Zou, W., Kumar, K. G., Fuchs, S. Y., Shuai, K., & Zhang, D. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601149 · Cited by 443
Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis
Wang, C., Li, Y., Shi, L., Ren, J., Patti, M., Wang, T., de Oliveira, J. R. M., Sobrido, M. J., Quintáns, B., Baquero, M., et al. (2012) · Nature Genetics · doi:10.1038/ng.1077 · Cited by 417
Self-citationWhat is and what is not ‘Fahr's disease’
Manyam, B. V. (2005) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2004.12.001 · Cited by 395
Interferon-Stimulated Gene 15 and the Protein ISGylation System
Zhang, D., & Zhang, D. (2010) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2010.0110 · Cited by 361
Durfee, L. A., Lyon, N., Seo, K., & Huibregtse, J. M. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.002 · Cited by 359
Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
Keller, A., Westenberger, A., Sobrido, M. J., García-Murias, M., Domingo, A., Sears, R. L., Lemos, R. R., Ordoñez-Ugalde, A., Nicolas, G., da Cunha, J. E. G., et al. (2013) · Nature Genetics · doi:10.1038/ng.2723 · Cited by 324
Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity
Crow, Y. J., & Rehwinkel, J. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp293 · Cited by 289
Self-citationMutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification
Nicolas, G., Pottier, C., Maltête, D., Coutant, S., Rovelet-Lecrux, A., Legallic, S., Rousseau, S., Vaschalde, Y., Guyant-Maréchal, L., Augustin, J., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e31827ccf34 · Cited by 279
François-Newton, V., Almeida, G. M. D. F., Payelle‐Brogard, B., Monneron, D., Pichard‐Garcia, L., Piehler, J., Pellegrini, S., & Uzé, G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022200 · Cited by 270
Self-citationThe Antiviral Activities of ISG15
Morales, D. J., & Lenschow, D. J. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.09.041 · Cited by 264
Briggs, T. A., Rice, G., Daly, S. B., Urquhart, J. E., Gornall, H., Bader‐Meunier, B., Baskar, K., Baskar, S., Baudouin, V., Beresford, M. W., et al. (2011) · Nature Genetics · doi:10.1038/ng.748 · Cited by 261
Self-citationEmerging Role of ISG15 in Antiviral Immunity
Skaug, B. A., & Chen, Z. J. (2010) · Cell · doi:10.1016/j.cell.2010.09.033 · Cited by 222
The Genetic Theory of Infectious Diseases: A Brief History and Selected Illustrations
Casanova, J., & Abel, L. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153448 · Cited by 193
Self-citationLi, Q. Z., Zhou, J., Wandstrat, A. E., Carr-Johnson, F., Branch, V. K., Karp, D. R., Mohan, C., Wakeland, E. K., & Olsen, N. J. (2006) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2006.03251.x · Cited by 189
Jeon, Y. J., Yoo, H. M., & Chung, C. H. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.02.006 · Cited by 175
Fine tuning type I interferon responses
Hertzog, P. J., & Williams, B. R. G. (2013) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2013.04.002 · Cited by 125
ISG15: leading a double life as a secreted molecule
Bogunovic, D., Boisson‐Dupuis, S., & Casanova, J. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.36 · Cited by 123
Self-citationCrow, Y. J. (2013) · Handbook of clinical neurology · doi:10.1016/b978-0-444-59565-2.00031-9 · Cited by 115
Self-citationBroering, R., Zhang, X., Kottilil, S., Trippler, M., Jiang, M., Lu, M., Gerken, G., & Schlaak, J. (2010) · Gut · doi:10.1136/gut.2009.195545 · Cited by 96
Self-citationBrain calcification in patients with cerebral lupus
Raymond, A. A., Zariah, A., Samad, S., Chin, C., & Kong, N. (1996) · Lupus · doi:10.1177/096120339600500207 · Cited by 87
Recognizable phenotypes associated with intracranial calcification
Livingston, J. H., Stivaros, S. M., van der Knaap, M. S., & Crow, Y. J. (2012) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.2012.04437.x · Cited by 78
Self-citationIntracranial calcification in paediatric computed tomography
Kendall, B. E., & Cavanagh, N. P. (1986) · Neuroradiology · doi:10.1007/bf00333438 · Cited by 61
The ISG15 Isopeptidase UBP43 Is Regulated by Proteolysis via the SCFSkp2 Ubiquitin Ligase
Tokarz, S. A., Berset, C., LaRUE, J. M., Friedman, K. M., Nakayama, K., Nakayama, K., Zhang, D., & Lanker, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403189200 · Cited by 58
USP18 establishes the transcriptional and anti-proliferative interferon α/β differential
François-Newton, V., Livingstone, M., Payelle‐Brogard, B., Uzé, G., & Pellegrini, S. (2012) · Biochemical Journal · doi:10.1042/bj20120541 · Cited by 54
Self-citationModulation of alpha interferon anti-hepatitis C virus activity by ISG15
Chua, P. K., McCown, M. F., Rajyaguru, S., Kular, S., Varma, R., Symons, J. A., Chiu, S. S., Cammack, N., & Nájera, I. (2009) · Journal of General Virology · doi:10.1099/vir.0.013128-0 · Cited by 44
Flagged first, then by citations
Cited by
Sorted by citations
New insights into the immunopathogenesis of systemic lupus erythematosus
Tsokos, G. C., Lo, M. S., Costa‐Reis, P., & Sullivan, K. E. (2016) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2016.186 · Cited by 1,251
Shared and Distinct Functions of Type I and Type III Interferons
Lazear, H. M., Schoggins, J. W., & Diamond, M. S. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.025 · Cited by 1,138
Aicardi–Goutières syndrome and the type I interferonopathies
Crow, Y. J., & Manel, N. (2015) · Nature Reviews Immunology · doi:10.1038/nri3850 · Cited by 925
Self-citationISG15 in antiviral immunity and beyond
Perng, Y.-C., & Lenschow, D. J. (2018) · Nature Reviews Microbiology · doi:10.1038/s41579-018-0020-5 · Cited by 855
The JAK-STAT pathway at 30: Much learned, much more to do
Philips, R. L., Wang, Y., Cheon, H., Kanno, Y., Gadina, M., Sartorelli, V., Horvath, C. M., Darnell, J. E., Jr., Stark, G. R., & O’Shea, J. J. (2022) · Cell · doi:10.1016/j.cell.2022.09.023 · Cited by 755
Metadata
- Authors
- Zhang, X., Bogunovic, D., Payelle-Brogard, B., Francois-Newton, V., Speer, S. D., Yuan, C., Volpi, S., Li, Z., Sanal, O., Mansouri, D., Tezcan, I., Rice, G. I., Chen, C., Mansouri, N., Mahdaviani, S. A., Itan, Y., Boisson, B., Okada, S., Zeng, L., Wang, X., Jiang, H., Liu, W., Han, T., Liu, D., Ma, T., Wang, B., Liu, M., Liu, J.-Y., Wang, Q. K., Yalnizoglu, D., Radoshevich, L., Uzé, G., Gros, P., Rozenberg, F., Zhang, S.-Y., Jouanguy, E., Bustamante, J., García-Sastre, A., Abel, L., Lebon, P., Notarangelo, L. D., Crow, Y. J., Boisson-Dupuis, S., Casanova, J.-L., & Pellegrini, S.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Boston Children's Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- Masih Daneshvari Hospital (IR)
- Manchester Academic Health Science Centre (GB)
- BGI Group (China) (CN)
- Hubei Provincial Women and Children's Hospital (CN)
- Cleveland Clinic (US)
- Institut Pasteur (FR)
- McGill University (CA)
- Université Paris Descartes (FR)
- Hôpital Necker-Enfants Malades (FR)
- Inserm (FR)
- Corresponding author
- Bogunovic, Dusan
- ORCID
- Zhang, Xianqin
- Bogunovic, Dusan
- Speer, Scott D.
- Yuan, Chao
- Volpi, Stefano
- Li, Zhi
- Mansouri, Davood
- Rice, Gillian I.
- Mansouri, Nahal
- Mahdaviani, Seyed Alireza
- Itan, Yuval
- Boisson, Bertrand
- Okada, Satoshi
- Zeng, Lu
- Wang, Xing
- Jiang, Hui
- Han, Tiantian
- Liu, Delin
- Ma, Tao
- Liu, Mugen
- Wang, Qing K.
- Radoshevich, Lilliana
- Uzé, Gilles
- Gros, Philippe
- Rozenberg, Flore
- Zhang, Shen-Ying
- Jouanguy, Emmanuelle
- Bustamante, Jacinta
- Abel, Laurent
- Notarangelo, Luigi D.
- Crow, Yanick J.
- Casanova, Jean-Laurent
- Pellegrini, Sandra
- Venue
- Nature
- Published
- 2014-10-12
- Volume
- 517
- Issue
- 7532
- Pages
- 89-93
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4303590
- OpenAlex
- W1601709990
- Cited by
- 558
- References
- 31
- Citations by year
- 2026: 45 · 2025: 36 · 2024: 56 · 2023: 57 · 2022: 43 · 2021: 49 · 2020: 57 · 2019: 35 · 2018: 36 · 2017: 58 · 2016: 43 · 2015: 42 · 2014: 1
- FWCI
- 20.31
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-02-11)
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
- IRIS (submittedVersion)
- Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- European Commission (200732, 241779, 2007–2013, FP7 2007-2013, FP7/2007, 223608)
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Greater Manchester Comprehensive Local Research Network
- National Institutes of Health (UL1TR000043, FP7/2007-2013)
- Manchester Biomedical Research Centre
- Japan Society for the Promotion of Science (25713039, 25670477)
- National Institute of Allergy and Infectious Diseases (P01AI076210, R01AI035237, P01AI090935, 1PO1AI076210-01A1, U19AI083025, R00AI106942, R37AI095983)
- National Center for Research Resources
- National Center for Advancing Translational Sciences
- FP7 Ideas: European Research Council (309449)
- CHIST-ERA
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- ISG15, USP18, type I interferon, autoinflammation, Aicardi-Goutières syndrome, interferonopathies, ISGylation, ubiquitin-like proteins, mycobacterial infection, interferon-gamma
- MeSH terms
- Adolescent, Alleles, Child, Female, Gene Expression Regulation, Humans, Inflammation, Interferon Type I, Male, Pedigree, Endopeptidases, Ubiquitins, Viruses, Signal Transduction, Cytokines, Intracellular Space, Ubiquitin Thiolesterase, S-Phase Kinase-Associated Proteins, Ubiquitination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
