FADD Phosphorylation Modulates Blood Glucose Levels by Decreasing the Expression of Insulin-Degrading Enzyme
Yan Lin1,2, Jia Liu1, Jia Chen1, Chun Yao1, Yunwen Yang1, Jie Wang1, Hongqin Zhuang1,*, and Zi-Chun Hua1,3,4,*
1The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China, 2School of Nursing, Xinxiang Medical University, Xinxiang 453000, China, 3Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou 213164, China, 4Shenzhen Research Institute of Nanjing University, Shenzhen 518057, China
Received August 28, 2019; Revised January 7, 2020; Accepted January 19, 2020.; Published online March 20, 2020.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

ABSTRACT
Our previous study revealed a novel role of Fas-associated death domain-containing protein (FADD) in islet development and insulin secretion. Insulin-degrading enzyme (IDE) is a zinc metalloprotease that selectively degrades biologically important substrates associated with type 2 diabetes (T2DM). The current study was designed to investigate the effect of FADD phosphorylation on IDE. We found that the mRNA and protein levels of IDE were significantly downregulated in FADD-D mouse livers compared with control mice. Quantitative real-time PCR analysis showed that FADD regulates the expression of IDE at the transcriptional level without affecting the stability of the mRNA in HepG2 cells. Following treatment with cycloheximide, the IDE protein degradation rate was found to be increased in both FADD-D primary hepatocytes and FADD-knockdown HepG2 cells. Additionally, IDE expression levels were reduced in insulin-stimulated primary hepatocytes from FADD-D mice compared to those from control mice. Moreover, FADD phosphorylation promotes nuclear translocation of FoxO1, thus inhibiting the transcriptional activity of the IDE promoter. Together, these findings imply a novel role of FADD in the reduction of protein stability and expression levels of IDE.
Keywords: FADD phosphorylation, FoxO1, insulin, insulin-degrading enzyme, protein stability


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31 March 2020 Volume 43,
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