Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors
Abstract Background Genetic variants in the subunits of the gamma-aminobutyric acid type A (GABAA) receptors are implicated in the onset of multiple pathologic conditions including genetic epilepsy. Previous work showed that pathogenic GABAA subunits promote misfolding and inefficient assembly of th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | Cell & Bioscience |
| Online Access: | https://doi.org/10.1186/s13578-022-00783-w |
| _version_ | 1811289225268559872 |
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| author | Meng Wang Edmund Cotter Ya-Juan Wang Xu Fu Angela L. Whittsette Joseph W. Lynch R. Luke Wiseman Jeffery W. Kelly Angelo Keramidas Ting-Wei Mu |
| author_facet | Meng Wang Edmund Cotter Ya-Juan Wang Xu Fu Angela L. Whittsette Joseph W. Lynch R. Luke Wiseman Jeffery W. Kelly Angelo Keramidas Ting-Wei Mu |
| author_sort | Meng Wang |
| collection | DOAJ |
| description | Abstract Background Genetic variants in the subunits of the gamma-aminobutyric acid type A (GABAA) receptors are implicated in the onset of multiple pathologic conditions including genetic epilepsy. Previous work showed that pathogenic GABAA subunits promote misfolding and inefficient assembly of the GABAA receptors, limiting receptor expression and activity at the plasma membrane. However, GABAA receptors containing variant subunits can retain activity, indicating that enhancing the folding, assembly, and trafficking of these variant receptors offers a potential opportunity to mitigate pathology associated with genetic epilepsy. Results Here, we demonstrate that pharmacologically enhancing endoplasmic reticulum (ER) proteostasis using small molecule activators of the ATF6 (Activating Transcription Factor 6) signaling arm of the unfolded protein response (UPR) increases the assembly, trafficking, and surface expression of variant GABAA receptors. These improvements are attributed to ATF6-dependent remodeling of the ER proteostasis environment, which increases protein levels of pro-folding ER proteostasis factors including the ER chaperone BiP (Immunoglobulin Binding Protein) and trafficking receptors, such as LMAN1 (Lectin Mannose-Binding 1) and enhances their interactions with GABAA receptors. Importantly, we further show that pharmacologic ATF6 activators increase the activity of GABAA receptors at the cell surface, revealing the potential for this strategy to restore receptor activity to levels that could mitigate disease pathogenesis. Conclusions These results indicate that pharmacologic ATF6 activators offer an opportunity to restore GABAA receptor activity in diseases including genetic epilepsy and point to the potential for similar pharmacologic enhancement of ER proteostasis to improve trafficking of other disease-associated variant ion channels implicated in etiologically-diverse diseases. |
| first_indexed | 2024-04-13T03:51:09Z |
| format | Article |
| id | doaj.art-569f39d2a4334662858040e0811c4d49 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-13T03:51:09Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-569f39d2a4334662858040e0811c4d492022-12-22T03:03:49ZengBMCCell & Bioscience2045-37012022-04-0112112010.1186/s13578-022-00783-wPharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptorsMeng Wang0Edmund Cotter1Ya-Juan Wang2Xu Fu3Angela L. Whittsette4Joseph W. Lynch5R. Luke Wiseman6Jeffery W. Kelly7Angelo Keramidas8Ting-Wei Mu9Department of Physiology and Biophysics, Case Western Reserve University School of MedicineQueensland Brain Institute, the University of QueenslandDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineQueensland Brain Institute, the University of QueenslandDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Molecular Medicine, The Scripps Research InstituteQueensland Brain Institute, the University of QueenslandDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineAbstract Background Genetic variants in the subunits of the gamma-aminobutyric acid type A (GABAA) receptors are implicated in the onset of multiple pathologic conditions including genetic epilepsy. Previous work showed that pathogenic GABAA subunits promote misfolding and inefficient assembly of the GABAA receptors, limiting receptor expression and activity at the plasma membrane. However, GABAA receptors containing variant subunits can retain activity, indicating that enhancing the folding, assembly, and trafficking of these variant receptors offers a potential opportunity to mitigate pathology associated with genetic epilepsy. Results Here, we demonstrate that pharmacologically enhancing endoplasmic reticulum (ER) proteostasis using small molecule activators of the ATF6 (Activating Transcription Factor 6) signaling arm of the unfolded protein response (UPR) increases the assembly, trafficking, and surface expression of variant GABAA receptors. These improvements are attributed to ATF6-dependent remodeling of the ER proteostasis environment, which increases protein levels of pro-folding ER proteostasis factors including the ER chaperone BiP (Immunoglobulin Binding Protein) and trafficking receptors, such as LMAN1 (Lectin Mannose-Binding 1) and enhances their interactions with GABAA receptors. Importantly, we further show that pharmacologic ATF6 activators increase the activity of GABAA receptors at the cell surface, revealing the potential for this strategy to restore receptor activity to levels that could mitigate disease pathogenesis. Conclusions These results indicate that pharmacologic ATF6 activators offer an opportunity to restore GABAA receptor activity in diseases including genetic epilepsy and point to the potential for similar pharmacologic enhancement of ER proteostasis to improve trafficking of other disease-associated variant ion channels implicated in etiologically-diverse diseases.https://doi.org/10.1186/s13578-022-00783-w |
| spellingShingle | Meng Wang Edmund Cotter Ya-Juan Wang Xu Fu Angela L. Whittsette Joseph W. Lynch R. Luke Wiseman Jeffery W. Kelly Angelo Keramidas Ting-Wei Mu Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors Cell & Bioscience |
| title | Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors |
| title_full | Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors |
| title_fullStr | Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors |
| title_full_unstemmed | Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors |
| title_short | Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors |
| title_sort | pharmacological activation of atf6 remodels the proteostasis network to rescue pathogenic gabaa receptors |
| url | https://doi.org/10.1186/s13578-022-00783-w |
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