GLP-1 Receptor Activation Abrogates β-Cell Dysfunction by PKA Cα-Mediated Degradation of Thioredoxin Interacting Protein

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He, ShijunSouthern Medical University, Guangzhou, China (author)

GLP-1 Receptor Activation Abrogates β-Cell Dysfunction by PKA Cα-Mediated Degradation of Thioredoxin Interacting Protein

Article/chapterEnglish2019

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2019-10-25
Frontiers Media SA,2019
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LIBRIS-ID:oai:DiVA.org:hh-48370
https://urn.kb.se/resolve?urn=urn:nbn:se:hh:diva-48370URI
https://doi.org/10.3389/fphar.2019.01230DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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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.

Subject headings and genre

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
PKA
Pancreatic beta cells
beta cell dysfunction
er stress
exendin 4

Added entries (persons, corporate bodies, meetings, titles ...)

Wu, WenyuSun Yat-sen University, Guangzhou, China (author)
Wan, YihongSouthern Medical University, Guangzhou, China (author)
Nandakumar, Kutty Selva,1965-Southern Medical University, Guangzhou, China(Swepub:hh)kutnam (author)
Cai, XiuchaoSouthern Medical University, Guangzhou, China (author)
Tang, XiaodongSouthern Medical University, Guangzhou, China (author)
Liu, ShuwenSouthern Medical University, Guangzhou, China: Southern Medical University, Foshan, China (author)
Yao, XingangSouthern Medical University, Guangzhou, China (author)
Southern Medical University, Guangzhou, ChinaSun Yat-sen University, Guangzhou, China (creator_code:org_t)

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In:Frontiers in Pharmacology: Frontiers Media SA101663-9812

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By the author/editor: He, Shijun; Wu, Wenyu; Wan, Yihong; Nandakumar, Kutt ...; Cai, Xiuchao; Tang, Xiaodong; show more...; Liu, Shuwen; Yao, Xingang; show less...

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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By the university: Halmstad University

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