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The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation

Nature Medicine volume 16, pages 429–437 (2010)Cite this article

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Abstract

Despite the fact that X-box binding protein-1 (XBP-1) is one of the main regulators of the unfolded protein response (UPR), the modulators of XBP-1 are poorly understood. Here, we show that the regulatory subunits of phosphotidyl inositol 3-kinase (PI3K), p85α (encoded by Pik3r1) and p85β (encoded by Pik3r2) form heterodimers that are disrupted by insulin treatment. This disruption of heterodimerization allows the resulting monomers of p85 to interact with, and increase the nuclear translocation of, the spliced form of XBP-1 (XBP-1s). The interaction between p85 and XBP-1s is lost in ob/ob mice, resulting in a severe defect in XBP-1s translocation to the nucleus and thus in the resolution of endoplasmic reticulum (ER) stress. These defects are ameliorated when p85α and p85β are overexpressed in the liver of ob/ob mice. Our results define a previously unknown insulin receptor signaling pathway and provide new mechanistic insight into the development of ER stress during obesity.

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Figure 1: p85α and p85β interact with XBP-1s.
Figure 2: p85α and p85β increase nuclear translocation of XBP-1s.
Figure 3: Insulin increases nuclear transport of XBP-1s.
Figure 4: XBP-1s import to the nucleus is impaired in the ob/ob mice.
Figure 5: Overexpression of p85α and p85β in the liver of ob/ob mice increases glucose tolerance and establishes euglycemia.
Figure 6: Nuclear translocation of XBP-1s is impaired in the liver-specific Pik3r1−/−;Pik3r2−/− mice.

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Acknowledgements

We thank members of the Ozcan laboratory for their contributions to this project. We are grateful to L. Cantley (Harvard Medical School) for kindly providing us with the Pik3r1f/f;Pik3r2−/− mice. We would like to thank the Children's Hospital Boston Proteomics Core Facility and H. Steen for the tandem mass spectroscopy analysis. This study was supported by junior faculty start-up funds provided to U.O. by Children's Hospital Boston, Translational Research Award, an RO1 grant (R01DK081009) provided to U.O., and Timothy Murphy funds provided to Division of Endocrinology, Children's Hospital Boston.

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Authors and Affiliations

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

    Sang Won Park, Yingjiang Zhou, Justin Lee, Allen Lu, Cheng Sun, Jason Chung & Umut Ozcan

  2. Department of Metabolic Disease, Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan.,

    Kohjiro Ueki

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Contributions

S.W.P. came up with the hypothesis, designed and performed the experiments, analyzed the data and wrote the manuscript. Y.Z., J.L., A.L., C.S. and J.C. performed the experiments. K.U. came up with the hypothesis and provided reagents. U.O. came up with the hypothesis, designed and performed the experiments, analyzed the data and wrote the manuscript.

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Correspondence to Kohjiro Ueki or Umut Ozcan.

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The authors declare no competing financial interests.

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Park, S., Zhou, Y., Lee, J. et al. The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation. Nat Med 16, 429–437 (2010). https://doi.org/10.1038/nm.2099

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