Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells
Abstract Group 2 innate lymphoid cells (ILC2s) are central effectors of type 2 immune responses in the lung; however, how mechanical cues regulate their function remains unclear. Here, we identified the mechanosensitive ion channel Piezo1 as a key regulator of ILC2 effector function through translat...
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| Format: | Article |
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Nature Publishing Group
2025-08-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02350-4 |
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| author | MinYeong Lim Seonjun Park Yoon Ha Joo Sung Eun Kim Min Hee Ham TaeSoo Kim Kihyuck Kwak Sung Joon Kim Jung Chan Lee Sung Ho Park Hye Young Kim |
| author_facet | MinYeong Lim Seonjun Park Yoon Ha Joo Sung Eun Kim Min Hee Ham TaeSoo Kim Kihyuck Kwak Sung Joon Kim Jung Chan Lee Sung Ho Park Hye Young Kim |
| author_sort | MinYeong Lim |
| collection | DOAJ |
| description | Abstract Group 2 innate lymphoid cells (ILC2s) are central effectors of type 2 immune responses in the lung; however, how mechanical cues regulate their function remains unclear. Here, we identified the mechanosensitive ion channel Piezo1 as a key regulator of ILC2 effector function through translational control. Piezo1 is highly expressed in murine and human ILC2s, and its activation by mechanical stress or the Piezo1 agonist, Yoda1 induces calcium influx, triggering mTOR signaling and selectively enhancing IL-13 protein production. Conditional deletion of Piezo1 in ILC2s reduced mTOR activation and puromycin incorporation, leading to impaired protein synthesis and attenuated lung inflammation and fibrosis in the IL-33, Alternaria alternata, and bleomycin models. scRNA-seq and scATAC-seq confirmed that Piezo1-deficient ILC2s retained Il13 transcription and chromatin accessibility but presented translational suppression, as evidenced by protein‒mRNA interactions. Pharmacologic mTOR inhibition phenocopied Piezo1 loss, supporting the functional relevance of the Piezo1–mTOR axis. These findings demonstrate that Piezo1 functions as a mechanosensor that integrates biomechanical cues to regulate cytokine output via mTOR-mediated translation. Targeting Piezo1 signaling or its downstream effectors may provide therapeutic benefits in type 2 inflammation–associated lung diseases. |
| format | Article |
| id | doaj-art-ef905384e6204966b2cb99913eea91e5 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
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| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-ef905384e6204966b2cb99913eea91e52025-08-24T11:54:00ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-08-0110111510.1038/s41392-025-02350-4Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cellsMinYeong Lim0Seonjun Park1Yoon Ha Joo2Sung Eun Kim3Min Hee Ham4TaeSoo Kim5Kihyuck Kwak6Sung Joon Kim7Jung Chan Lee8Sung Ho Park9Hye Young Kim10Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of MedicineDepartment of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST)Interdisciplinary Program in Bioengineering, Graduate School, Seoul National UniversityDepartment of Neurology, Division of Sleep Medicine, Harvard Medical School and Beth Israel Deaconess Medical CenterDepartment of Microbiology and Immunology, College of Medicine, Yonsei UniversityDepartment of Life Science, Multitasking Macrophage Research Center, Ewha Womans UniversityDepartment of Microbiology and Immunology, College of Medicine, Yonsei UniversityDepartment of Physiology, College of Medicine, Seoul National UniversityDepartment of Biomedical Engineering, College of Medicine, Seoul National UniversityDepartment of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST)Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of MedicineAbstract Group 2 innate lymphoid cells (ILC2s) are central effectors of type 2 immune responses in the lung; however, how mechanical cues regulate their function remains unclear. Here, we identified the mechanosensitive ion channel Piezo1 as a key regulator of ILC2 effector function through translational control. Piezo1 is highly expressed in murine and human ILC2s, and its activation by mechanical stress or the Piezo1 agonist, Yoda1 induces calcium influx, triggering mTOR signaling and selectively enhancing IL-13 protein production. Conditional deletion of Piezo1 in ILC2s reduced mTOR activation and puromycin incorporation, leading to impaired protein synthesis and attenuated lung inflammation and fibrosis in the IL-33, Alternaria alternata, and bleomycin models. scRNA-seq and scATAC-seq confirmed that Piezo1-deficient ILC2s retained Il13 transcription and chromatin accessibility but presented translational suppression, as evidenced by protein‒mRNA interactions. Pharmacologic mTOR inhibition phenocopied Piezo1 loss, supporting the functional relevance of the Piezo1–mTOR axis. These findings demonstrate that Piezo1 functions as a mechanosensor that integrates biomechanical cues to regulate cytokine output via mTOR-mediated translation. Targeting Piezo1 signaling or its downstream effectors may provide therapeutic benefits in type 2 inflammation–associated lung diseases.https://doi.org/10.1038/s41392-025-02350-4 |
| spellingShingle | MinYeong Lim Seonjun Park Yoon Ha Joo Sung Eun Kim Min Hee Ham TaeSoo Kim Kihyuck Kwak Sung Joon Kim Jung Chan Lee Sung Ho Park Hye Young Kim Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells Signal Transduction and Targeted Therapy |
| title | Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells |
| title_full | Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells |
| title_fullStr | Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells |
| title_full_unstemmed | Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells |
| title_short | Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells |
| title_sort | piezo1 mediated mechanotransduction regulates the translational activity function and lung pathogenicity of group 2 innate lymphoid cells |
| url | https://doi.org/10.1038/s41392-025-02350-4 |
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