PKA phosphorylation couples hepatic inositol-requiring enzyme 1[alpha] to glucagon signaling in glucose metabolism
The endoplasmic reticulum (ER)-resident protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) is activated through transautophosphorylation in response to protein folding overload in the ER lumen and maintains ER homeostasis by triggering a key branch of the unfolded protein response. H...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-09, Vol.108 (38), p.15852 |
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creator | Mao, Ting Shao, Mengle Qiu, Yifu Huang, Jialiang Zhang, Yongliang Song, Bo Wang, Qiong Jiang, Lei Liu, Yi Han, Jing-Dong J Cao, Pengrong Li, Jia Gao, Xiang Rui, Liangyou Qi, Ling Li, Wenjun Liu, Yong |
description | The endoplasmic reticulum (ER)-resident protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) is activated through transautophosphorylation in response to protein folding overload in the ER lumen and maintains ER homeostasis by triggering a key branch of the unfolded protein response. Here we show that mammalian IRE1α in liver cells is also phosphorylated by a kinase other than itself in response to metabolic stimuli. Glucagon-stimulated protein kinase PKA, which in turn phosphorylated IRE1α at Ser..., a highly conserved site within the kinase activation domain. Blocking Ser... phosphorylation impaired the ability of IRE1α to augment the up-regulation by glucagon signaling of the expression of gluconeogenic genes. Moreover, hepatic IRE1α was highly phosphorylated at Ser... by PKA in mice with obesity, and silencing hepatic IRE1α markedly reduced hyperglycemia and glucose intolerance. Hence, these results suggest that IRE1α integrates signals from both the ER lumen and the cytoplasm in the liver and is coupled to the glucagon signaling in the regulation of glucose metabolism. (ProQuest: ... denotes formulae/symbols omitted.) |
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Here we show that mammalian IRE1α in liver cells is also phosphorylated by a kinase other than itself in response to metabolic stimuli. Glucagon-stimulated protein kinase PKA, which in turn phosphorylated IRE1α at Ser..., a highly conserved site within the kinase activation domain. Blocking Ser... phosphorylation impaired the ability of IRE1α to augment the up-regulation by glucagon signaling of the expression of gluconeogenic genes. Moreover, hepatic IRE1α was highly phosphorylated at Ser... by PKA in mice with obesity, and silencing hepatic IRE1α markedly reduced hyperglycemia and glucose intolerance. Hence, these results suggest that IRE1α integrates signals from both the ER lumen and the cytoplasm in the liver and is coupled to the glucagon signaling in the regulation of glucose metabolism. 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subjects | Cytoplasm Homeostasis Kinases Liver Phosphorylation |
title | PKA phosphorylation couples hepatic inositol-requiring enzyme 1[alpha] to glucagon signaling in glucose metabolism |
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