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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01230

GLP-1 receptor activation abrogates -cell dysfunction by PKA C-mediated degradation of thioredoxin interacting protein

  • 1Southern Medical University, China
  • 2Zhongshan Ophthalmic Center, Sun Yat-sen University, China
  • 3School of Pharmaceutical Sciences, Southern Medical University, China

Glucagon-like peptide 1 receptor (GLP-1R) agonist (Exendin-4) is a well-known agents to improve -cell dysfunctions via protein kinase A (PKA), but the detailed downstream molecular mechanisms are still elusive. Now we found that PKA C mediated- TXNIP phosphorylation and degradation played a vital role in the -cell protective role of exendin-4. After PKA activator (Exendin-4 or FSK) treatment, PKA C could directly interact with TXNIP by bimolecular fluorescence complementation and Co-IP assays in INS-1 cells. And PKA C overexpression decreased TXNIP level, whereas TXNIP level was largely increased in PKA C-KO -cells by CRISPR-Cas9. Interestingly, TXNIP overexpression or PKA C-KO has impaired -cell functions, including loss of insulin secretion and activation of inflammation. PKA C directly phosphorylated TXNIP at Ser307 and Ser308 positions, leading to its degradation via activation of cellular proteasome pathway. In consistent with this observation, TXNIP (S307/308A) mutant resisted the degradation effects of PKA C. However, exendin-4 affected neither TXNIP level in TXNIP (S307/308A) mutant overexpressed -cells nor in PKA C-KO -cells. Moreover, exendin-4 treatment reduced the inflammation gene expression in TXNIP overexpressed -cells, but exendin-4 treatment has no effect on the inflammation gene expression in TXNIP (S307/308A) overexpressed -cells. In conclusion, our study reveals integral role of PKA C/TXNIP signaling in pancreatic β-cells and suggests that PKA C-mediated TXNIP degradation is vital in -cell protective effects of exendin-4.

Keywords: exendin 4, PKA, Pancreatic beta cells, er stress, beta cell dysfunction, TXNIP (thioredoxin-interacting protein)

Received: 22 Jul 2019; Accepted: 27 Sep 2019.

Copyright: © 2019 He, Wu, Wan, Nandakumar, Cai, Tang, Liu and Yao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Xin G. Yao, Southern Medical University, Guangzhou, China, yaoxingang@smu.edu.cn