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Wang, X. ; Zhang, H.* ; Wang, Y.* ; Bramasole, L.* ; Guo, K.* ; Mourtada, F.* ; Meul, T. ; Hu, Q. ; Viteri-Alvarez, V. ; Kammerl, I.E. ; Königshoff, M. ; Lehmann, M. ; Magg, T.* ; Hauck, F.* ; Fernandez, I.E. ; Meiners, S.

DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity.

EMBO J. 42:e110597 (2023)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8+ T cells. The cGAS/STING-induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men. In patients with idiopathic pulmonary fibrosis, chronic activation of the cGAS/STING-induced adaptive immune response in aberrant lung epithelial cells concurs with CD8+ T-cell activation in diseased lungs. Genetic depletion of the immunoproteasome and specific immunoproteasome inhibitors counteract DNA stress induced cytotoxic CD8+ T-cell activation. Our data thus unravel cytoplasmic DNA sensing via the cGAS/STING pathway as an activator of the immunoproteasome and CD8+ T cells. This represents a novel potential pathomechanism for pulmonary fibrosis that opens new therapeutic perspectives.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cd8+ T Cells ; Cgas/sting ; Fibrosis ; Immunoproteasome ; Mitochondria; Mitochondrial-dna; Molecular Mimicry; Proteasome; Innate; Mechanisms; Inhibitor; Mice; Autoimmunity; Homeostasis; Expression
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 42, Heft: 8, Seiten: , Artikelnummer: e110597 Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
POF Topic(s) 30202 - Environmental Health
80000 - German Center for Lung Research
Forschungsfeld(er) Lung Research
PSP-Element(e) G-501600-004
G-503100-001
G-501600-006
G-501800-816
G-501800-803
G-501600-001
Förderungen
Projekt DEAL
German Bundesinstitut fuer Risikobewertung
LMU Medical Faculty, Munich, Germany
Munich Clinician Scientist Program (MCSP)
China Postdoctoral Science Foundation
National Natural Science Foundation of China
Guangzhou Elite Scholarship Council (GESC)
DOI 10.15252/embj.2022110597
WOS ID 000948322900001
Scopus ID 85149783031
PubMed ID 36912165
Erfassungsdatum 2023-10-06
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