title: PKA phosphorylation couples hepatic inositol-requiring enzyme 1alpha to glucagon signaling in glucose metabolism.
abstract: 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(724), a highly conserved site within the kinase activation domain. Blocking Ser(724) 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(724) 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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Mao
authors.forename: Mengle
authors.initials: M
authors.lastname: Shao
authors.forename: Yifu
authors.initials: Y
authors.lastname: Qiu
authors.forename: Jialiang
authors.initials: J
authors.lastname: Huang
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Song
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
authors.forename: Pengrong
authors.initials: P
authors.lastname: Cao
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005934:Glucagon / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D012694:Serine; D005934:Glucagon; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D004722:Endoribonucleases; D005947:Glucose