14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cells
While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3z in b-ce...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022
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| _version_ | 1797106816594739200 |
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| author | Mugabo, Y Zhao, C Tan, JJ Ghosh, A Campbell, SA Fadzeyeva, E Paré, F Pan, SS Galipeau, M Ast, J Broichhagen, J Hodson, DJ Broichhagen, J Mulvihill, EE Petropoulos, S Lim, GE |
| author_facet | Mugabo, Y Zhao, C Tan, JJ Ghosh, A Campbell, SA Fadzeyeva, E Paré, F Pan, SS Galipeau, M Ast, J Broichhagen, J Hodson, DJ Broichhagen, J Mulvihill, EE Petropoulos, S Lim, GE |
| author_sort | Mugabo, Y |
| collection | OXFORD |
| description | While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant
functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have
been implicated in regulating metabolism. We previously reported contributions of 14-3-3z in b-cell
function, but these studies were performed in tumor-derived MIN6 cells and systemic knockout mice. To
further characterize the regulatory roles of 14-3-3-z in b-cell function, we generated b-cell-specific 14-3-3z
knockout mice. Although no effects on b-cell mass were detected, potentiated glucose-stimulated insulin
secretion (GSIS), mitochondrial function, and ATP synthesis were observed. 14-3-3z deletion also altered
the b-cell transcriptome, as genes associated with mitochondrial respiration and oxidative phosphorylation
were upregulated. Acute 14-3-3 protein inhibition in mouse and human islets recapitulated the
enhancements in GSIS and mitochondrial function, suggesting that 14-3-3z is the critical isoform in bcells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of
Ywhaz/YWHAZ, the gene encoding 14-3-3z, was inversely associated with insulin secretion, and pan-14-
3-3 protein inhibition led to enhanced GSIS and mitochondrial function. Taken together, this study
demonstrates important regulatory functions of 14-3-3z in the regulation of b-cell function and provides a
deeper understanding of how insulin secretion is controlled in b-cells. |
| first_indexed | 2024-03-07T07:06:17Z |
| format | Journal article |
| id | oxford-uuid:818e0c4a-3791-4e6b-9c76-f7a4dcece48d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:06:17Z |
| publishDate | 2022 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | oxford-uuid:818e0c4a-3791-4e6b-9c76-f7a4dcece48d2022-05-13T12:05:45Z14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:818e0c4a-3791-4e6b-9c76-f7a4dcece48dEnglishSymplectic ElementsAmerican Society for Clinical Investigation2022Mugabo, YZhao, CTan, JJGhosh, ACampbell, SAFadzeyeva, EParé, FPan, SSGalipeau, MAst, JBroichhagen, JHodson, DJBroichhagen, JMulvihill, EEPetropoulos, SLim, GEWhile critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3z in b-cell function, but these studies were performed in tumor-derived MIN6 cells and systemic knockout mice. To further characterize the regulatory roles of 14-3-3-z in b-cell function, we generated b-cell-specific 14-3-3z knockout mice. Although no effects on b-cell mass were detected, potentiated glucose-stimulated insulin secretion (GSIS), mitochondrial function, and ATP synthesis were observed. 14-3-3z deletion also altered the b-cell transcriptome, as genes associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute 14-3-3 protein inhibition in mouse and human islets recapitulated the enhancements in GSIS and mitochondrial function, suggesting that 14-3-3z is the critical isoform in bcells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3z, was inversely associated with insulin secretion, and pan-14- 3-3 protein inhibition led to enhanced GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3z in the regulation of b-cell function and provides a deeper understanding of how insulin secretion is controlled in b-cells. |
| spellingShingle | Mugabo, Y Zhao, C Tan, JJ Ghosh, A Campbell, SA Fadzeyeva, E Paré, F Pan, SS Galipeau, M Ast, J Broichhagen, J Hodson, DJ Broichhagen, J Mulvihill, EE Petropoulos, S Lim, GE 14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cells |
| title | 14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cells |
| title_full | 14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cells |
| title_fullStr | 14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cells |
| title_full_unstemmed | 14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cells |
| title_short | 14-3-3z constrains insulin secretion by regulating mitochondrial function in pancreatic b-cells |
| title_sort | 14 3 3z constrains insulin secretion by regulating mitochondrial function in pancreatic b cells |
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