Insulin inhibits hepatic glucose production through activation of the protein kinase Akt, and any defect in this pathway causes fasting hyperglycaemia in Type 2 diabetes. APPL1 [adaptor protein, phosphotyrosine interaction, PH (pleckstrin homology) domain and leucine zipper containing 1] sensitizes hepatic insulin action on suppression of gluconeogenesis by binding to Akt. However, the mechanisms underlying the insulin-sensitizing actions of APPL1 remain elusive. In the present study we show that insulin induces Lys63-linked ubiquitination of APPL1 in primary hepatocytes and in the livers of C57 mice. Lys160 located within the BAR (Bin/amphiphysin/Rvs) domain of APPL1 is the major site for its ubiquitination. Replacement of Lys160 with arginine abolishes insulin-dependent ubiquitination and membrane localization of APPL1, and also diminishes membrane recruitment and activation of Akt, thereby abrogating the effects of APPL1 on alleviation of hepatic insulin resistance and glucose intolerance in obese mice. Further analysis identified TRAF6 (tumour-necrosis-factor-receptor-associated factor 6) as an E3 ubiquitin ligase for APPL1 ubiquitination. Suppression of TRAF6 expression attenuates insulin-mediated ubiquitination and membrane targeting of APPL1, leading to an impairment of insulin-stimulated Akt activation and inhibition of gluconeogenesis in hepatocytes. Thus TRAF6-mediated ubiquitination of APPL1 is a vital step for the hepatic actions of insulin through modulation of membrane trafficking and activity of Akt.
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Research Article|
September 27 2013
TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt
Kenneth K. Y. Cheng;
Kenneth K. Y. Cheng
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
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Karen S. L. Lam;
Karen S. L. Lam
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
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Yu Wang;
Yu Wang
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
‡Department of Pharmacology & Pharmacy, University of Hong Kong, L2-53, 21 Sassoon Road, Hong Kong
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Donghai Wu;
Donghai Wu
§The Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
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Mingliang Zhang;
Mingliang Zhang
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
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Baile Wang;
Baile Wang
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
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Xiaomu Li;
Xiaomu Li
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
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Ruby L. C. Hoo;
Ruby L. C. Hoo
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
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Zhe Huang;
Zhe Huang
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
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Gary Sweeney;
Gary Sweeney
∥Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3
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Aimin Xu
Aimin Xu
1
*Department of Medicine, University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong
†State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Hong Kong
‡Department of Pharmacology & Pharmacy, University of Hong Kong, L2-53, 21 Sassoon Road, Hong Kong
1To whom correspondence should be addressed (email amxu@hku.hk).
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Publisher: Portland Press Ltd
Received:
June 10 2013
Revision Received:
August 05 2013
Accepted:
August 05 2013
Accepted Manuscript online:
August 05 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 455 (2): 207–216.
Article history
Received:
June 10 2013
Revision Received:
August 05 2013
Accepted:
August 05 2013
Accepted Manuscript online:
August 05 2013
Citation
Kenneth K. Y. Cheng, Karen S. L. Lam, Yu Wang, Donghai Wu, Mingliang Zhang, Baile Wang, Xiaomu Li, Ruby L. C. Hoo, Zhe Huang, Gary Sweeney, Aimin Xu; TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt. Biochem J 15 October 2013; 455 (2): 207–216. doi: https://doi.org/10.1042/BJ20130760
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