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DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity.
EMBO J. 42:e110597 (2023)
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
ISSN (print) / ISBN
0261-4189
e-ISSN
1460-2075
Zeitschrift
EMBO Journal, The
Quellenangaben
Band: 42,
Heft: 8,
Artikelnummer: e110597
Verlag
Wiley
Verlagsort
Heidelberg, Germany
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Lung Health and Immunity (LHI)
Research Unit Lung Repair and Regeneration (LRR)
Institute of Lung Biology (LHI)
Research Unit Lung Repair and Regeneration (LRR)
Institute of Lung Biology (LHI)
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)
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)