Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization.
Cyclic adenosine monophosphate (cAMP), a ubiquitous second messenger, regulates a variety of cellular functions with high specificity. We previously showed that the type I regulatory subunit of cAMP-dependent protein kinase A (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) to facilitate...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3003262 |
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| author | Ha Neul Lee Julia C Hardy Emily H Pool Jin-Fan Zhang Su Hyun Kim William F Buhl Jessica G H Bruystens Sohum Mehta Susan S Taylor Jin Zhang |
| author_facet | Ha Neul Lee Julia C Hardy Emily H Pool Jin-Fan Zhang Su Hyun Kim William F Buhl Jessica G H Bruystens Sohum Mehta Susan S Taylor Jin Zhang |
| author_sort | Ha Neul Lee |
| collection | DOAJ |
| description | Cyclic adenosine monophosphate (cAMP), a ubiquitous second messenger, regulates a variety of cellular functions with high specificity. We previously showed that the type I regulatory subunit of cAMP-dependent protein kinase A (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) to facilitate spatial compartmentalization of cAMP. However, how RIα LLPS regulates cellular function is largely unknown. Here, we identify the formation of RIα condensates in MIN6 β cells and reveal key roles for RIα LLPS in regulating β cell function. By combining CRISPR-based RIα knockout with an RIα mutant (Y122A) that exhibits defective cAMP-induced LLPS, we demonstrate that RIα LLPS drives cAMP compartmentalization to tune β cell Ca2+ and cAMP oscillation frequency, control insulin secretion, regulate CREB-mediated gene expression and prevent uncontrolled proliferation. Our data establish the Y122A mutant as a selective molecular tool for studying RIα LLPS and expand our understanding of the functional impact of LLPS-driven protein assemblies. |
| format | Article |
| id | doaj-art-51bbf9d8224e4afea035cf2c0f1d0ec4 |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-51bbf9d8224e4afea035cf2c0f1d0ec42025-08-20T03:57:59ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-07-01237e300326210.1371/journal.pbio.3003262Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization.Ha Neul LeeJulia C HardyEmily H PoolJin-Fan ZhangSu Hyun KimWilliam F BuhlJessica G H BruystensSohum MehtaSusan S TaylorJin ZhangCyclic adenosine monophosphate (cAMP), a ubiquitous second messenger, regulates a variety of cellular functions with high specificity. We previously showed that the type I regulatory subunit of cAMP-dependent protein kinase A (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) to facilitate spatial compartmentalization of cAMP. However, how RIα LLPS regulates cellular function is largely unknown. Here, we identify the formation of RIα condensates in MIN6 β cells and reveal key roles for RIα LLPS in regulating β cell function. By combining CRISPR-based RIα knockout with an RIα mutant (Y122A) that exhibits defective cAMP-induced LLPS, we demonstrate that RIα LLPS drives cAMP compartmentalization to tune β cell Ca2+ and cAMP oscillation frequency, control insulin secretion, regulate CREB-mediated gene expression and prevent uncontrolled proliferation. Our data establish the Y122A mutant as a selective molecular tool for studying RIα LLPS and expand our understanding of the functional impact of LLPS-driven protein assemblies.https://doi.org/10.1371/journal.pbio.3003262 |
| spellingShingle | Ha Neul Lee Julia C Hardy Emily H Pool Jin-Fan Zhang Su Hyun Kim William F Buhl Jessica G H Bruystens Sohum Mehta Susan S Taylor Jin Zhang Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization. PLoS Biology |
| title | Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization. |
| title_full | Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization. |
| title_fullStr | Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization. |
| title_full_unstemmed | Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization. |
| title_short | Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization. |
| title_sort | phase separation of a pka type i regulatory subunit regulates β cell function through camp compartmentalization |
| url | https://doi.org/10.1371/journal.pbio.3003262 |
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