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p38 MAPK–mediated regulation of Xbp1s is crucial for glucose homeostasis

Nature Medicine volume 17, pages 12511260 (2011) | Download Citation

Abstract

Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.

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Acknowledgements

We thank members of the Ozcan laboratory for their help during the execution of the experiments. We thank L. Glimcher (Harvard School of Public Health) for providing us with the Xbp1flox/flox mouse strain. We thank P. Blackshear (National Institute of Environment Health Sciences) for kindly providing us with Zfp36−/− cells and M. Gaestel (Hannover Medical School, Germany) for generously providing Mapkapk2−/− cells. We thank R. Davis (University of Massachusetts Medical School) for providing Mapk8−/−; Mapk9−/−, Map2k3−/−; Map2k6−/−, Map2k4−/−; Map2k7−/− and Mapk14−/− MEFs as well as their wild-type control MEFs. We are grateful to H. Feldman (Harvard Medical School) for helping us with the statistical analysis. This study was supported by the junior faculty start-up funds provided to U.O. by Children's Hospital Boston, an RO1 grant (R01DK081009) and R56 grant (R56DK089111) provided to U.O. by the US National Institutes of Health and the Timothy Murphy funds provided to the Division of Endocrinology, Children's Hospital Boston.

Author information

Author notes

    • Jaemin Lee
    •  & Cheng Sun

    These authors contributed equally to this work.

Affiliations

  1. Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.

    • Jaemin Lee
    • , Cheng Sun
    • , Yingjiang Zhou
    • , Justin Lee
    • , Deniz Gokalp
    • , Hilde Herrema
    • , Sang Won Park
    •  & Umut Ozcan
  2. Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Roger J Davis

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Contributions

Jaemin Lee and C.S. designed and carried out the experiments, analyzed the data and wrote the manuscript. Y.Z., Justin Lee, D.G., H.H., S.W.P. did the experiments. R.J.D. provided reagents and advice through out the project. U.O. developed the hypothesis, designed experiments, analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Umut Ozcan.

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DOI

https://doi.org/10.1038/nm.2449

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