Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells
CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in β-...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/21/15994 |
| _version_ | 1797631759999827968 |
|---|---|
| author | Mirabela Hali Nelson Pinto Noah Gleason Anjaneyulu Kowluru |
| author_facet | Mirabela Hali Nelson Pinto Noah Gleason Anjaneyulu Kowluru |
| author_sort | Mirabela Hali |
| collection | DOAJ |
| description | CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in β-cells following exposure to HG and GLT stress. The current study is aimed at understanding the putative roles of histone deacetylation in HG- and GLT-induced expression of CARD9. Using two structurally distinct inhibitors of histone deacetylases (HDACs), namely trichostatin (TSA) and suberoylanilide hydroxamic acid (SAHA), we provide the first evidence to suggest that the increased expression of CARD9 seen under duress of HG and GLT stress is under the regulatory control of histone deacetylation. Interestingly, the expression of protein kinase Cδ (PKCδ), a known upstream regulator of CARD9 activation, is also increased under conditions of metabolic stress. However, it is resistant to TSA and SAHA, suggesting that it is not regulated via histone deacetylation. Based on these data, we propose that targeting the appropriate HDACs, which mediate the expression (and function) of CARD9, might be the next step to further enhance our current understanding of the roles of CARD9 in islet dysfunction under metabolic stress and diabetes. |
| first_indexed | 2024-03-11T11:27:56Z |
| format | Article |
| id | doaj.art-f11e64b40b614f6a8d7ab68dc39b6109 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:27:56Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f11e64b40b614f6a8d7ab68dc39b61092023-11-10T15:06:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124211599410.3390/ijms242115994Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-CellsMirabela Hali0Nelson Pinto1Noah Gleason2Anjaneyulu Kowluru3Biomedical Research Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USABiomedical Research Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USABiomedical Research Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USABiomedical Research Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USACARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in β-cells following exposure to HG and GLT stress. The current study is aimed at understanding the putative roles of histone deacetylation in HG- and GLT-induced expression of CARD9. Using two structurally distinct inhibitors of histone deacetylases (HDACs), namely trichostatin (TSA) and suberoylanilide hydroxamic acid (SAHA), we provide the first evidence to suggest that the increased expression of CARD9 seen under duress of HG and GLT stress is under the regulatory control of histone deacetylation. Interestingly, the expression of protein kinase Cδ (PKCδ), a known upstream regulator of CARD9 activation, is also increased under conditions of metabolic stress. However, it is resistant to TSA and SAHA, suggesting that it is not regulated via histone deacetylation. Based on these data, we propose that targeting the appropriate HDACs, which mediate the expression (and function) of CARD9, might be the next step to further enhance our current understanding of the roles of CARD9 in islet dysfunction under metabolic stress and diabetes.https://www.mdpi.com/1422-0067/24/21/15994histone deacetylase inhibitorsCARD9pancreatic islet β-cellTSA and SAHA |
| spellingShingle | Mirabela Hali Nelson Pinto Noah Gleason Anjaneyulu Kowluru Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells International Journal of Molecular Sciences histone deacetylase inhibitors CARD9 pancreatic islet β-cell TSA and SAHA |
| title | Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells |
| title_full | Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells |
| title_fullStr | Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells |
| title_full_unstemmed | Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells |
| title_short | Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells |
| title_sort | regulatory roles of histone deacetylation in metabolic stress induced expression of caspase recruitment domain containing protein 9 card9 in pancreatic β cells |
| topic | histone deacetylase inhibitors CARD9 pancreatic islet β-cell TSA and SAHA |
| url | https://www.mdpi.com/1422-0067/24/21/15994 |
| work_keys_str_mv | AT mirabelahali regulatoryrolesofhistonedeacetylationinmetabolicstressinducedexpressionofcaspaserecruitmentdomaincontainingprotein9card9inpancreaticbcells AT nelsonpinto regulatoryrolesofhistonedeacetylationinmetabolicstressinducedexpressionofcaspaserecruitmentdomaincontainingprotein9card9inpancreaticbcells AT noahgleason regulatoryrolesofhistonedeacetylationinmetabolicstressinducedexpressionofcaspaserecruitmentdomaincontainingprotein9card9inpancreaticbcells AT anjaneyulukowluru regulatoryrolesofhistonedeacetylationinmetabolicstressinducedexpressionofcaspaserecruitmentdomaincontainingprotein9card9inpancreaticbcells |