The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics
The cytoskeleton has a primary role in cardiomyocyte function, including the response to mechanical stimuli and injury. The small heat shock protein 20 (Hsp20) conveys protective effects in cardiac muscle that are linked to serine-16 (Ser16) Hsp20 phosphorylation by stress-induced PKA, but the link...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/24/9572 |
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| author | Elizabeth Vafiadaki Demetrios A. Arvanitis Aristides G. Eliopoulos Evangelia G. Kranias Despina Sanoudou |
| author_facet | Elizabeth Vafiadaki Demetrios A. Arvanitis Aristides G. Eliopoulos Evangelia G. Kranias Despina Sanoudou |
| author_sort | Elizabeth Vafiadaki |
| collection | DOAJ |
| description | The cytoskeleton has a primary role in cardiomyocyte function, including the response to mechanical stimuli and injury. The small heat shock protein 20 (Hsp20) conveys protective effects in cardiac muscle that are linked to serine-16 (Ser16) Hsp20 phosphorylation by stress-induced PKA, but the link between Hsp20 and the cytoskeleton remains poorly understood. Herein, we demonstrate a physical and functional interaction of Hsp20 with the cytoskeletal protein 14-3-3. We show that, upon phosphorylation at Ser16, Hsp20 translocates from the cytosol to the cytoskeleton where it binds to 14-3-3. This leads to dissociation of 14-3-3 from the F-actin depolymerization regulator cofilin-2 (CFL2) and enhanced F-actin depolymerization. Importantly, we demonstrate that the P20L Hsp20 mutation associated with dilated cardiomyopathy exhibits reduced physical interaction with 14-3-3 due to diminished Ser16 phosphorylation, with subsequent failure to translocate to the cytoskeleton and inability to disassemble the 14-3-3/CFL2 complex. The topological sequestration of Hsp20 P20L ultimately results in impaired regulation of F-actin dynamics, an effect implicated in loss of cytoskeletal integrity and amelioration of the cardioprotective functions of Hsp20. These findings underscore the significance of Hsp20 phosphorylation in the regulation of actin cytoskeleton dynamics, with important implications in cardiac muscle physiology and pathophysiology. |
| first_indexed | 2024-03-10T14:01:54Z |
| format | Article |
| id | doaj.art-41c9128779464b16aa1c95323e6e7bb9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:01:54Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-41c9128779464b16aa1c95323e6e7bb92023-11-21T00:59:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012124957210.3390/ijms21249572The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal DynamicsElizabeth Vafiadaki0Demetrios A. Arvanitis1Aristides G. Eliopoulos2Evangelia G. Kranias3Despina Sanoudou4Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, GreeceMolecular Biology Division, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, GreeceMolecular Biology Division, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, GreeceMolecular Biology Division, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, GreeceMolecular Biology Division, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, GreeceThe cytoskeleton has a primary role in cardiomyocyte function, including the response to mechanical stimuli and injury. The small heat shock protein 20 (Hsp20) conveys protective effects in cardiac muscle that are linked to serine-16 (Ser16) Hsp20 phosphorylation by stress-induced PKA, but the link between Hsp20 and the cytoskeleton remains poorly understood. Herein, we demonstrate a physical and functional interaction of Hsp20 with the cytoskeletal protein 14-3-3. We show that, upon phosphorylation at Ser16, Hsp20 translocates from the cytosol to the cytoskeleton where it binds to 14-3-3. This leads to dissociation of 14-3-3 from the F-actin depolymerization regulator cofilin-2 (CFL2) and enhanced F-actin depolymerization. Importantly, we demonstrate that the P20L Hsp20 mutation associated with dilated cardiomyopathy exhibits reduced physical interaction with 14-3-3 due to diminished Ser16 phosphorylation, with subsequent failure to translocate to the cytoskeleton and inability to disassemble the 14-3-3/CFL2 complex. The topological sequestration of Hsp20 P20L ultimately results in impaired regulation of F-actin dynamics, an effect implicated in loss of cytoskeletal integrity and amelioration of the cardioprotective functions of Hsp20. These findings underscore the significance of Hsp20 phosphorylation in the regulation of actin cytoskeleton dynamics, with important implications in cardiac muscle physiology and pathophysiology.https://www.mdpi.com/1422-0067/21/24/9572Hsp20 phosphorylation14-3-3actin cytoskeletoncardiac musclecardiomyopathyheart failure |
| spellingShingle | Elizabeth Vafiadaki Demetrios A. Arvanitis Aristides G. Eliopoulos Evangelia G. Kranias Despina Sanoudou The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics International Journal of Molecular Sciences Hsp20 phosphorylation 14-3-3 actin cytoskeleton cardiac muscle cardiomyopathy heart failure |
| title | The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics |
| title_full | The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics |
| title_fullStr | The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics |
| title_full_unstemmed | The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics |
| title_short | The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics |
| title_sort | cardioprotective pka mediated hsp20 phosphorylation modulates protein associations regulating cytoskeletal dynamics |
| topic | Hsp20 phosphorylation 14-3-3 actin cytoskeleton cardiac muscle cardiomyopathy heart failure |
| url | https://www.mdpi.com/1422-0067/21/24/9572 |
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