Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations
Open accessAbstract
Innate immunity to viral infection involves induction of the type I IFN response; however, dysfunctional regulation of this pathway leads to inappropriate inflammation. Here, we evaluated a nonconsanguineous family of mixed European descent, with 4 members affected by systemic inflammatory and autoimmune conditions, including lupus, with variable clinical expression. We identified a germline dominant gain-of-function mutation in TMEM173, which encodes stimulator of type I IFN gene (STING), in the affected individuals. STING is a key signaling molecule in cytosolic DNA-sensing pathways, and STING activation normally requires dimerization, which is induced by 2'3' cyclic GMP-AMP (cGAMP) produced by the cGAMP synthase in response to cytosolic DNA. Structural modeling supported constitutive activation of the mutant STING protein based on stabilized dimerization. In agreement with the model predictions, we found that the STING mutant spontaneously localizes in the Golgi of patient fibroblasts and is constitutively active in the absence of exogenous 2'3'-cGAMP in vitro. Accordingly, we observed elevated serum IFN activity and a type I IFN signature in peripheral blood from affected family members. These findings highlight the key role of STING in activating both the innate and adaptive immune responses and implicate aberrant STING activation in features of human lupus.
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Rare STING gain-of-function mutations are associated with massive inflammation especially in lungs.
“Conversely, rare STING gain-of-function mutations are associated with massive inflammation especially in lungs (88).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [88]
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- Authors
- Jeremiah, N., Neven, B., Gentili, M., Callebaut, I., Maschalidi, S., Stolzenberg, M.-C., Goudin, N., Frémond, M.-L., Nitschke, P., Molina, T. J., Blanche, S., Picard, C., Rice, G. I., Crow, Y. J., Manel, N., Fischer, A., Bader-Meunier, B., & Rieux-Laucat, F.
- Affiliations
- Inserm (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Manchester Academic Health Science Centre (GB)
- Corresponding author
- Neven, Bénédicte
- Gentili, Matteo
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-11-17
- Volume
- 124
- Issue
- 12
- Pages
- 5516-5520
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4348945
- OpenAlex
- W1966408457
- Cited by
- 562
- References
- 21
- Citations by year
- 2026: 30 · 2025: 48 · 2024: 52 · 2023: 48 · 2022: 62 · 2021: 62 · 2020: 54 · 2019: 60 · 2018: 39 · 2017: 42 · 2016: 35 · 2015: 28 · 2014: 1
- FWCI
- 16.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Styrelsen för Internationellt Utvecklingssamarbete
- Fondation Arthritis
- Fondation Acteria
- Institut des maladies génétiques Imagine (ANR-10-IAHU- 01)
- Agence Nationale de la Recherche (ANR-14-CE14-0026, CE14-0026-01, ANR-10-IAHU- 01, 249816, ANR-10-IAHU-0001, 10-IAHU-01, ANR-10)
- Institut National de la Santé et de la Recherche Médicale (ANR‐10‐IAHU‐01, 249816)
- Fondation ARC pour la Recherche sur le Cancer
- FP7 Ideas: European Research Council (309848)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- STING, gain-of-function mutations, type I interferonopathy, type I interferon response, cGAMP, cytosolic DNA sensing, Golgi localization, autoimmunity, innate immunity
- MeSH terms
- STING Protein, Adult, Aged, Child, Preschool, Female, Humans, Immunity, Innate, Interferon Type I, Lupus Erythematosus, Systemic, Male, Membrane Proteins, Mutation, Nucleotides, Cyclic, Syndrome, Signal Transduction, Genetic Diseases, Inborn, Protein Multimerization, Adaptive Immunity
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