LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment
Abstract Periodontal ligament stem cells (PDLSCs) are a key cell type for restoring/regenerating lost/damaged periodontal tissues, including alveolar bone, periodontal ligament and root cementum, the latter of which is important for regaining tooth function. However, PDLSCs residing in an inflammato...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-03-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-022-00197-x |
| _version_ | 1818319794524389376 |
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| author | Xuan Li Bei-Min Tian Dao-Kun Deng Fen Liu Huan Zhou De-Qin Kong Hong-Lei Qu Li-Juan Sun Xiao-Tao He Fa-Ming Chen |
| author_facet | Xuan Li Bei-Min Tian Dao-Kun Deng Fen Liu Huan Zhou De-Qin Kong Hong-Lei Qu Li-Juan Sun Xiao-Tao He Fa-Ming Chen |
| author_sort | Xuan Li |
| collection | DOAJ |
| description | Abstract Periodontal ligament stem cells (PDLSCs) are a key cell type for restoring/regenerating lost/damaged periodontal tissues, including alveolar bone, periodontal ligament and root cementum, the latter of which is important for regaining tooth function. However, PDLSCs residing in an inflammatory environment generally exhibit compromised functions, as demonstrated by an impaired ability to differentiate into cementoblasts, which are responsible for regrowing the cementum. This study investigated the role of mitochondrial function and downstream long noncoding RNAs (lncRNAs) in regulating inflammation-induced changes in the cementogenesis of PDLSCs. We found that the inflammatory cytokine-induced impairment of the cementogenesis of PDLSCs was closely correlated with their mitochondrial function, and lncRNA microarray analysis and gain/loss-of-function studies identified GACAT2 as a regulator of the cellular events involved in inflammation-mediated mitochondrial function and cementogenesis. Subsequently, a comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) and parallel reaction monitoring (PRM) assays revealed that GACAT2 could directly bind to pyruvate kinase M1/2 (PKM1/2), a protein correlated with mitochondrial function. Further functional studies demonstrated that GACAT2 overexpression increased the cellular protein expression of PKM1/2, the PKM2 tetramer and phosphorylated PKM2, which led to enhanced pyruvate kinase (PK) activity and increased translocation of PKM2 into mitochondria. We then found that GACAT2 overexpression could reverse the damage to mitochondrial function and cementoblastic differentiation of PDLSCs induced by inflammation and that this effect could be abolished by PKM1/2 knockdown. Our data indicated that by binding to PKM1/2 proteins, the lncRNA GACAT2 plays a critical role in regulating mitochondrial function and cementogenesis in an inflammatory environment. |
| first_indexed | 2024-12-13T10:14:47Z |
| format | Article |
| id | doaj.art-f1061bd2e07d45c6a5a9f9677a0ac9e3 |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-12-13T10:14:47Z |
| publishDate | 2022-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-f1061bd2e07d45c6a5a9f9677a0ac9e32022-12-21T23:51:21ZengNature Publishing GroupBone Research2095-62312022-03-0110111510.1038/s41413-022-00197-xLncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environmentXuan Li0Bei-Min Tian1Dao-Kun Deng2Fen Liu3Huan Zhou4De-Qin Kong5Hong-Lei Qu6Li-Juan Sun7Xiao-Tao He8Fa-Ming Chen9State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityDepartment of Toxicology, Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityState Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityAbstract Periodontal ligament stem cells (PDLSCs) are a key cell type for restoring/regenerating lost/damaged periodontal tissues, including alveolar bone, periodontal ligament and root cementum, the latter of which is important for regaining tooth function. However, PDLSCs residing in an inflammatory environment generally exhibit compromised functions, as demonstrated by an impaired ability to differentiate into cementoblasts, which are responsible for regrowing the cementum. This study investigated the role of mitochondrial function and downstream long noncoding RNAs (lncRNAs) in regulating inflammation-induced changes in the cementogenesis of PDLSCs. We found that the inflammatory cytokine-induced impairment of the cementogenesis of PDLSCs was closely correlated with their mitochondrial function, and lncRNA microarray analysis and gain/loss-of-function studies identified GACAT2 as a regulator of the cellular events involved in inflammation-mediated mitochondrial function and cementogenesis. Subsequently, a comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) and parallel reaction monitoring (PRM) assays revealed that GACAT2 could directly bind to pyruvate kinase M1/2 (PKM1/2), a protein correlated with mitochondrial function. Further functional studies demonstrated that GACAT2 overexpression increased the cellular protein expression of PKM1/2, the PKM2 tetramer and phosphorylated PKM2, which led to enhanced pyruvate kinase (PK) activity and increased translocation of PKM2 into mitochondria. We then found that GACAT2 overexpression could reverse the damage to mitochondrial function and cementoblastic differentiation of PDLSCs induced by inflammation and that this effect could be abolished by PKM1/2 knockdown. Our data indicated that by binding to PKM1/2 proteins, the lncRNA GACAT2 plays a critical role in regulating mitochondrial function and cementogenesis in an inflammatory environment.https://doi.org/10.1038/s41413-022-00197-x |
| spellingShingle | Xuan Li Bei-Min Tian Dao-Kun Deng Fen Liu Huan Zhou De-Qin Kong Hong-Lei Qu Li-Juan Sun Xiao-Tao He Fa-Ming Chen LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment Bone Research |
| title | LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment |
| title_full | LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment |
| title_fullStr | LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment |
| title_full_unstemmed | LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment |
| title_short | LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment |
| title_sort | lncrna gacat2 binds with protein pkm1 2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment |
| url | https://doi.org/10.1038/s41413-022-00197-x |
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