Abstract
Glucagon-like peptide 1 receptor (GLP-1R) agonist (Exendin-4) is a well-known agent used to improve β-cell dysfunctions via protein kinase A (PKA), but the detailed downstream molecular mechanisms are still elusive. We have now found that PKA Cα mediated- TXNIP phosphorylation and degradation played a vital role in the β-cell protective role of exendin-4. After PKA activator (Exendin-4 or FSK) treatment, PKA Cα could directly interact with TXNIP by bimolecular fluorescence complementation and Co-IP assays in INS-1 cells. And PKA Cα overexpression decreased TXNIP level, whereas TXNIP level was largely increased in PKA Cα-KO β-cells by CRISPR-Cas9. Interestingly, TXNIP overexpression or PKA Cα-KO has impaired β-cell functions, including loss of insulin secretion and activation of inflammation. PKA Cα directly phosphorylated TXNIP at Ser307 and Ser308 positions, leading to its degradation via activation of cellular proteasome pathway. Consistent with this observation, TXNIP (S307/308A) mutant resisted the degradation effects of PKA Cα. However, exendin-4 neither affected TXNIP level in TXNIP (S307/308A) mutant overexpressed β-cells nor in PKA Cα-KO β-cells. Moreover, exendin-4 treatment reduced the inflammation gene expression in TXNIP overexpressed β-cells, but exendin-4 treatment has no effect on the inflammation gene expression in TXNIP (S307/308A) overexpressed β-cells. In conclusion, our study reveals the integral role of PKA Cα/TXNIP signaling in pancreatic β-cells and suggests that PKA Cα-mediated TXNIP degradation is vital in β-cell protective effects of exendin-4.
Highlights
The prevalence of type 2 diabetes (T2D) in human beings has been increasing over recent several decades (Gao et al, 2016; Zheng et al, 2018)
We demonstrated that exendin-4 or FSK (PKA activator) could alleviate Endoplasmic reticulum (ER) stressinduced β-cell dysfunctions through protein kinase A (PKA) Cα mediated thioredoxin-interacting protein (TXNIP) degradation pathway
Earlier studies reported the effects of exendin-4 on TXNIP, our results demonstrated the crucial role of PKA Cα-mediated TXNIP phosphorylation on the β-cell protective effects of exendin-4 for the first time
Summary
The prevalence of type 2 diabetes (T2D) in human beings has been increasing over recent several decades (Gao et al, 2016; Zheng et al, 2018). Endoplasmic reticulum (ER) stress is a major underlying cause of T2D, indicated by increasing evidence, and following pancreatic β-cell dysfunctions (Laybutt et al, 2007; Shang et al, 2014). As pro-insulin is processed to mature insulin in ER, the enhancement of insulin production puts a stress on ER functions and leads to the activation of ER stress and the unfolded protein response in the pancreatic β-cells. Recent studies indicate β-cell inflammasome activation induced by ER stress, and following IL-1β production, which could cause a feedback loop to enlarge inflammatory responses, leading to cell damage (Szpigel et al, 2018)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
