RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21
Abstract Background Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown. Methods Utilizing in vivo gene manipulations in mice, primary murine car...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-02-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-04985-3 |
| _version_ | 1797273477122621440 |
|---|---|
| author | Abhishek Singh Sengar Manish Kumar Chetna Rai Sreemoyee Chakraborti Dinesh Kumar Pranesh Kumar Sukhes Mukherjee Kausik Mondal Adele Stewart Biswanath Maity |
| author_facet | Abhishek Singh Sengar Manish Kumar Chetna Rai Sreemoyee Chakraborti Dinesh Kumar Pranesh Kumar Sukhes Mukherjee Kausik Mondal Adele Stewart Biswanath Maity |
| author_sort | Abhishek Singh Sengar |
| collection | DOAJ |
| description | Abstract Background Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown. Methods Utilizing in vivo gene manipulations in mice, primary murine cardiac cells, human cell lines and human patient samples we dissect the participation of a RGS6-nucleolin complex in chemotherapy-dependent cardiotoxicity. Results Here we demonstrate that RGS6 binds to a key nucleolar protein, Nucleolin, and controls its expression and activity in cardiomyocytes. In the human myocyte AC-16 cell line, induced pluripotent stem cell derived cardiomyocytes, primary murine cardiomyocytes, and the intact murine myocardium tuning RGS6 levels via overexpression or knockdown resulted in diametrically opposed impacts on Nucleolin mRNA, protein, and phosphorylation.RGS6 depletion provided marked protection against nucleolar stress-mediated cell death in vitro, and, conversely, RGS6 overexpression suppressed ribosomal RNA production, a key output of the nucleolus, and triggered death of myocytes. Importantly, overexpression of either Nucleolin or Nucleolin effector miRNA-21 counteracted the pro-apoptotic effects of RGS6. In both human and murine heart tissue, exposure to the genotoxic stressor doxorubicin was associated with an increase in the ratio of RGS6/Nucleolin. Preventing RGS6 induction via introduction of RGS6-directed shRNA via intracardiac injection proved cardioprotective in mice and was accompanied by restored Nucleolin/miRNA-21 expression, decreased nucleolar stress, and decreased expression of pro-apoptotic, hypertrophy, and oxidative stress markers in heart. Conclusion Together, these data implicate RGS6 as a driver of nucleolar stress-dependent cell death in cardiomyocytes via its ability to modulate Nucleolin. This work represents the first demonstration of a functional role for an RGS protein in the nucleolus and identifies the RGS6/Nucleolin interaction as a possible new therapeutic target in the prevention of cardiotoxicity. |
| first_indexed | 2024-03-07T14:43:52Z |
| format | Article |
| id | doaj.art-96d75244a0374e72ae4e20f8b8dbcf04 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-07T14:43:52Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-96d75244a0374e72ae4e20f8b8dbcf042024-03-05T20:06:31ZengBMCJournal of Translational Medicine1479-58762024-02-0122111810.1186/s12967-024-04985-3RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21Abhishek Singh Sengar0Manish Kumar1Chetna Rai2Sreemoyee Chakraborti3Dinesh Kumar4Pranesh Kumar5Sukhes Mukherjee6Kausik Mondal7Adele Stewart8Biswanath Maity9Centre of Biomedical Research (CBMR)Centre of Biomedical Research (CBMR)Centre of Biomedical Research (CBMR)Centre of Biomedical Research (CBMR)Centre of Biomedical Research (CBMR)Institute of Pharmaceutical Science, University of LucknowBiochemistry, AIIMS BhopalZoology, University of KalyaniBiomedical Science, Florida Atlantic UniversityCentre of Biomedical Research (CBMR)Abstract Background Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown. Methods Utilizing in vivo gene manipulations in mice, primary murine cardiac cells, human cell lines and human patient samples we dissect the participation of a RGS6-nucleolin complex in chemotherapy-dependent cardiotoxicity. Results Here we demonstrate that RGS6 binds to a key nucleolar protein, Nucleolin, and controls its expression and activity in cardiomyocytes. In the human myocyte AC-16 cell line, induced pluripotent stem cell derived cardiomyocytes, primary murine cardiomyocytes, and the intact murine myocardium tuning RGS6 levels via overexpression or knockdown resulted in diametrically opposed impacts on Nucleolin mRNA, protein, and phosphorylation.RGS6 depletion provided marked protection against nucleolar stress-mediated cell death in vitro, and, conversely, RGS6 overexpression suppressed ribosomal RNA production, a key output of the nucleolus, and triggered death of myocytes. Importantly, overexpression of either Nucleolin or Nucleolin effector miRNA-21 counteracted the pro-apoptotic effects of RGS6. In both human and murine heart tissue, exposure to the genotoxic stressor doxorubicin was associated with an increase in the ratio of RGS6/Nucleolin. Preventing RGS6 induction via introduction of RGS6-directed shRNA via intracardiac injection proved cardioprotective in mice and was accompanied by restored Nucleolin/miRNA-21 expression, decreased nucleolar stress, and decreased expression of pro-apoptotic, hypertrophy, and oxidative stress markers in heart. Conclusion Together, these data implicate RGS6 as a driver of nucleolar stress-dependent cell death in cardiomyocytes via its ability to modulate Nucleolin. This work represents the first demonstration of a functional role for an RGS protein in the nucleolus and identifies the RGS6/Nucleolin interaction as a possible new therapeutic target in the prevention of cardiotoxicity.https://doi.org/10.1186/s12967-024-04985-3CardiotoxicityG-proteinRGS proteinsChemotherapyNucleolar stress |
| spellingShingle | Abhishek Singh Sengar Manish Kumar Chetna Rai Sreemoyee Chakraborti Dinesh Kumar Pranesh Kumar Sukhes Mukherjee Kausik Mondal Adele Stewart Biswanath Maity RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21 Journal of Translational Medicine Cardiotoxicity G-protein RGS proteins Chemotherapy Nucleolar stress |
| title | RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21 |
| title_full | RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21 |
| title_fullStr | RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21 |
| title_full_unstemmed | RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21 |
| title_short | RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21 |
| title_sort | rgs6 drives cardiomyocyte death following nucleolar stress by suppressing nucleolin mirna 21 |
| topic | Cardiotoxicity G-protein RGS proteins Chemotherapy Nucleolar stress |
| url | https://doi.org/10.1186/s12967-024-04985-3 |
| work_keys_str_mv | AT abhisheksinghsengar rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT manishkumar rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT chetnarai rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT sreemoyeechakraborti rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT dineshkumar rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT praneshkumar rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT sukhesmukherjee rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT kausikmondal rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT adelestewart rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 AT biswanathmaity rgs6drivescardiomyocytedeathfollowingnucleolarstressbysuppressingnucleolinmirna21 |