p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis
Program in Molecular Medicine
Active Transport, Cell Nucleus; Analysis of Variance; Animals; Blood Glucose; Cells, Cultured; Chromatography, Liquid; DNA-Binding Proteins; Fibroblasts; Gene Knockout Techniques; Homeostasis; Humans; Liver; MAP Kinase Kinase 3; MAP Kinase Kinase 6; Mice; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase Kinases; Mutation; Obesity; Phosphorylation; Tandem Mass Spectrometry; Transcription Factors; p38 Mitogen-Activated Protein Kinases
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
DOI of Published Version
Nat Med. 2011 Sep 4;17(10):1251-60. doi: 10.1038/nm.2449. Link to article on publisher's site
Lee, Jaemin; Sun, Cheng; Zhou, Yingjiang; Lee, Justin; Gokalp, Deniz; Herrema, Hilde; Park, Sang Won.; Davis, Roger J.; and Ozcan, Umut, "p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis" (2011). Davis Lab Publications. 44.