Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca PPP3/calcineurin-TFEB axis
Journal article
Authors | Zummo, F.P, Krishnanda, S.I, Georgiou, M., O’Harte, F. P. M., Parthsarathy, V., Cullen, K.S, Honkanen-Scott, M, Shaw, J.A.M, Lovat, P.E and Arden, C |
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Abstract | Macroautophagy/autophagy is critical for the regulation of pancreatic β-cell mass and its deregulation has been implicated in the pathogenesis of type 2 diabetes (T2D). We have previously shown that treatment of pancreatic β-cells with the GLP1R (glucagon like peptide 1 receptor) agonist exendin-4 stimulates autophagic flux in a setting of chronic nutrient excess. The aim of this study was to identify the underlying pathways contributing to enhanced autophagic flux.Pancreatic β-cells (INS-1E),mouse and human islets were treated with glucolipotoxic stress (0.5 mM palmitate and 25 mM glucose) in the presence of exendin-4. Consistent with our previous work, exendin-4 stimulated autophagic flux. Using chemical inhibitors and siRNA knockdown, we identified RAPGEF4/EPAC2 (Rap guanine nucleotide exchange factor 4) and downstream calcium signaling to be essential for regulation of autophagic flux by exendin-4. This pathway was independent of AMPK and MTOR signaling. Further analysis identified PPP3/calcineurin and its downstream regulator TFEB (transcription factor EB) as key proteins mediating exendin-4 induced autophagy. Importantly, inhibition of this pathway prevented exendin-4-mediated cell survival and overexpression of TFEB mimicked the cell protective effects of exendin-4 in INS-1E and human islets. Moreover, treatment of db/db mice with exendin-4 for 21 days increased the expression of lysosomal markers within the pancreatic islets. Collectively our data identify the RAPGEF4/EPAC2-calcium-PPP3/calcineurin-TFEB axis as a key mediator of autophagic flux, lysosomal function and cell survival in pancreatic β-cells. Pharmacological modulation of this axis may offer a novel therapeutic target for the treatment of T2D.Abbreviations: AKT1/protein kinase B: AKT serine/threonine kinase 1; AMPK: 5' AMP-activated protein kinase; CAMKK: calcium/calmodulin-dependent protein kinase kinase; cAMP: cyclic adenosine monophosphate; CASP3: caspase 3; CREB: cAMP response element-binding protein; CTSD: cathepsin D; Ex4: exendin-4(1-39); GLP-1: glucagon like peptide 1; GLP1R: glucagon like peptide 1 receptor; GLT: glucolipotoxicity; INS: insulin; MTOR: mechanistic target of rapamycin kinase; NFAT: nuclear factor of activated T-cells; PPP3/calcineurin: protein phosphatase 3; PRKA/PKA: protein kinase cAMP activated; RAPGEF3/EPAC1: Rap guanine nucleotide exchange factor 3; RAPGEF4/EPAC2: Rap guanine nucleotide exchange factor 4; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TFEB: transcription factor EB. |
Keywords | Autophagy; GLP1R agonists; PPP3/calcineurin |
Year | 2021 |
Journal | Autophagy |
Journal citation | 18 (4), pp. 1-17 |
Publisher | Taylor & Francis Group plc |
ISSN | 1554-8635 |
Digital Object Identifier (DOI) | https://doi.org/10.1080/15548627.2021.1956123 |
Web address (URL) | https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1956123 |
https://pubmed.ncbi.nlm.nih.gov/34338148/ | |
Funder | Diabetes UK |
Wellcome Trust | |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 02 Aug 2021 |
Publication process dates | |
Accepted | 12 Jul 2021 |
Deposited | 04 Jan 2023 |
https://repository.derby.ac.uk/item/9vz6q/exendin-4-stimulates-autophagy-in-pancreatic-cells-via-the-rapgef-epac-ca-ppp3-calcineurin-tfeb-axis
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