期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2114557118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Stromal-interacting molecule 1 (STIM1) proteins are essential for the function of store-operated Ca
2+ entry (SOCE). Using transcriptomics, metabolomics, imaging, and inducible smooth muscle–specific STIM1 knockout mice expressing genetically encoded Ca
2+ sensors, we reveal a crucial function of STIM1 in airway remodeling and airway hyperresponsiveness in asthma. STIM1-mediated Ca
2+ oscillations in airway smooth muscle (ASM) cells are critical for ASM remodeling through metabolic and transcriptional reprogramming and cytokine secretion, including IL-6. These effects are driven by Ca
2+-dependent activation of the transcription factor isoform NFAT4 specifically in ASM. Our data provide evidence that ASM STIM1 and SOCE are central triggers of asthma manifestations and advocate for the future use of STIM1 as a molecular target in asthma therapy.
Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca
2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca
2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca
2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.
