Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 217, Issue 5, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20192319
Keywords
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Categories
Funding
- National Institute of Allergy and Infectious Diseases [R01AI127372, R21AI134366, R21AI129827]
- T32 training grant at the Icahn School of Medicine at Mount Sinai [5T32HD075735-07]
- Poste d'accueil INSERM
- F31 training grant at the Icahn School of Medicine at Mount Sinai [5F31AI138363]
- St. Giles Foundation
- Jeffrey Model Foundation
- Rockefeller University Center for Clinical and Translational Science (National Center for Research Resources and National Center for Advancing Translational Sciences grant) [8UL1TR000043]
- National Institutes of Health (National Institute of Allergy and Infectious Diseases grants) [5R01AI089970-02, 5R37AI095983]
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- Fondation pour la Recherche Medicale [ANR-10IAHU-01]
- French National Research Agency under the Investments for the future program [ANR-10IAHU-01]
- GENMSMD [ANR-16-CE17-0005-01]
- Institut National de la Sante et de la Recherche Medicale
- Paris Descartes University
- Rockefeller University
- March of Dimes
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Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN- I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I-stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.
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