title: Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species.
abstract: Dysregulation in cellular redox systems results in accumulation of reactive oxygen species (ROS), which are causally associated with a number of disease conditions. Transforming growth factor β-activated kinase 1 (TAK1) is a signaling intermediate of innate immune signaling pathways and is critically involved in the redox regulation in vivo. Ablation of TAK1 causes accumulation of ROS, resulting in epithelial cell death and inflammation. Here we determine the mechanism by which TAK1 kinase is activated in epithelial tissues. TAB1 and TAB2 are structurally unrelated TAK1 binding protein partners. TAB2 is known to mediate polyubiquitin chain-dependent TAK1 activation in innate immune signaling pathways, whereas the role of TAB1 is not defined. We found that epithelial-specific TAB1 and TAB2 double- but not TAB1 or TAB2 single-knockout mice phenocopied epithelial-specific TAK1 knockout mice. We demonstrate that phosphorylation-dependent basal activity of TAK1 is dependent on TAB1. Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues. These results demonstrate that epithelial TAK1 activity is regulated through two unique, TAB1-dependent basal and TAB2-mediated stimuli-dependent mechanisms.
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Omori
authors.forename: Maiko
authors.initials: M
authors.lastname: Inagaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D004817:Epidermis / Q000201:enzymology; D004847:Epithelial Cells / Q000201:enzymology*; D007413:Intestinal Mucosa / Q000201:enzymology; D015603:Keratinocytes / Q000201:enzymology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020930:MAP Kinase Kinase Kinases; D017382:Reactive Oxygen Species; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse; C498761:Tab2 protein, mouse