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The Asthma Risk Gene, GSDMB, Promotes Mitochondrial DNA-induced ISGs Expression

Journal of Respiratory Biology and Translational Medicine . 2024, 1(1), 10005; https://doi.org/10.35534/jrbtm.2024.10005
Tao Liu 1    Julian Hecker 1    Siqi Liu 1    Xianliang Rui 1    Nathan Boyer 1    Jennifer Wang 1    Yuzhen Yu 1    Yihan Zhang 2    Hongmei Mou 2    Luis Guillermo Gomez-Escobar 3    Augustine M.K. Choi 3    Benjamin A. Raby 4    Scott T. Weiss 1    Xiaobo Zhou 1 *   
1
Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
2
The Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA
3
Weil Cornell Medical School, Joan and Sanford I. Weill Department of Medicine, New York, NY 10065, USA
4
Division of Pulmonary Medicine, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
*
Authors to whom correspondence should be addressed.

Received: 27 Feb 2024    Accepted: 22 Mar 2024    Published: 31 Mar 2024   

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Abstract

Released mitochondrial DNA (mtDNA) in cells activates cGAS-STING pathway, which induces expression of interferon-stimulated genes (ISGs) and thereby promotes inflammation, as frequently seen in asthmatic airways. However, whether the genetic determinant, Gasdermin B (GSDMB), the most replicated asthma risk gene, regulates this pathway remains unknown. We set out to determine whether and how GSDMB regulates mtDNA-activated cGAS-STING pathway and subsequent ISGs induction in human airway epithelial cells. Using qPCR, ELISA, native polyacrylamide gel electrophoresis, co-immunoprecipitation and immunofluorescence assays, we evaluated the regulation of GSDMB on cGAS-STING pathway in both BEAS-2B cells and primary normal human bronchial epithelial cells (nHBEs). mtDNA was extracted in plasma samples from human asthmatics and the correlation between mtDNA levels and eosinophil counts was analyzed. GSDMB is significantly associated with RANTES expression in asthmatic nasal epithelial brushing samples from the Genes-environments and Admixture in Latino Americans (GALA) II study. Over-expression of GSDMB promotes DNA-induced IFN and ISGs expression in bronchial epithelial BEAS-2B cells and nHBEs. Conversely, knockout of GSDMB led to weakened induction of interferon (IFNs) and ISGs in BEAS-2B cells. Mechanistically, GSDMB interacts with the C-terminus of STING, promoting the translocalization of STING to Golgi, leading to the phosphorylation of IRF3 and induction of IFNs and ISGs. mtDNA copy number in serum from asthmatics was significantly correlated with blood eosinophil counts especially in male subjects. GSDMB promotes the activation of mtDNA and poly (dA:dT)-induced activation of cGAS-STING pathway in airway epithelial cells, leading to enhanced induction of ISGs.

Keywords

cGAS-STING pathway, GSDMB, ISGs, Asthma, Airway inflammation

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