التفاصيل البيبلوغرافية
| العنوان: |
Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes |
| المؤلفون: |
Giulia Maria Piperno, Asma Naseem, Giulia Silvestrelli, Roberto Amadio, Nicoletta Caronni, Karla Evelia Cervantes-Luevano, Nalan Liv, Judith Klumperman, Andrea Colliva, Hashim Ali, Francesca Graziano, Philippe Benaroch, Hans Haecker, Richard N. Hanna, Federica Benvenuti |
| المصدر: |
JCI Insight, Vol 5, Iss 17 (2020) |
| بيانات النشر: |
American Society for Clinical investigation, 2020. |
| سنة النشر: |
2020 |
| المجموعة: |
LCC:Medicine |
| مصطلحات موضوعية: |
Cell biology, Immunology, Medicine |
| الوصف: |
Dysregulated sensing of self–nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self–nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2379-3708 |
| Relation: |
https://doaj.org/toc/2379-3708 |
| DOI: |
10.1172/jci.insight.132857 |
| URL الوصول: |
https://doaj.org/article/61132181a0f44b3abc254bbae0684a5e |
| رقم الانضمام: |
edsdoj.61132181a0f44b3abc254bbae0684a5e |
| قاعدة البيانات: |
Directory of Open Access Journals |
Full Text Finder