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

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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Figure 1: SAPK signaling increases Xbp1s mRNA stability and nuclear translocation.
Figure 2: p38 MAPK increases mRNA stability of Xbp1s through activation of MK2.
Figure 3: p38 MAPK phosphorylates Xbp1s at Thr48 and Ser61.
Figure 4: Inhibition of p38 MAPK blocks Xbp1s nuclear translocation.
Figure 5: Reactivation of p38 MAPK in the liver of ob/ob mice greatly enhances Xbp1s nuclear translocation.
Figure 6: Xbp1s–T48A-S61A cannot migrate to the nucleus in the liver and regulate glucose homeostasis.

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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.

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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.

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Correspondence to Umut Ozcan.

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Lee, J., Sun, C., Zhou, Y. et al. p38 MAPK–mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat Med 17, 1251–1260 (2011). https://doi.org/10.1038/nm.2449

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