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

The activation of stress kinases, such as p38 MAPK, is believed to be detrimental to normal cellular processes. However, Umut Ozcan and his colleagues now show that p38 MAPK is actually beneficial, as in mice it increases the mRNA stability and nuclear localization of Xbp1s, a crucial factor in resolving endoplasmic reticulum stress and improving glucose homeostasis. These results suggest a possible indirect way of targeting XBP1s in the treatment of type 2 diabetes. 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.