TAK1 binding protein 2 is essential for liver protection from stressors.
The liver is the first line of defense from environmental stressors in that hepatocytes respond to and metabolize them. Hence, hepatocytes can be damaged by stressors. Protection against hepatic cell damage and cell death is important for liver function and homeostasis. TAK1 (MAP3K7) is an intermediate of stressors such as bacterial moieties-induced signal transduction pathways in several cell types. Tak1 deficiency has been reported to induce spontaneous hepatocellular carcinoma. However, the regulatory mechanism of TAK1 activity in liver stress response has not yet been defined. Here we report that activation of TAK1 through TAK1 binding protein 2 (TAB2) is required for liver protection from stressors. We found that a bacterial moiety, lipopolysaccharides (LPS), activated TAK1 in primary hepatocytes, which was diminished by deletion of TAB2. Mice having hepatocyte-specific deletion of the Tab2 gene exhibited only late-onset moderate liver lesions but were hypersensitive to LPS-induced liver injury. Furthermore, we show that a chemical stressor induced greatly exaggerated liver injury in hepatocyte-specific Tab2-deficient mice. These results demonstrate that TAB2 is a sensor of stress conditions in the liver and functions to protect the liver by activating the TAK1 pathway.
Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Yuka
Y
Ikeda
Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Sho
S
Morioka
Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan.
Kunihiro
K
Matsumoto
Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Jun
J
Ninomiya-Tsuji
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004052:Diethylnitrosamine / Q000633:toxicity*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D000477:Alkylating Agents; D004052:Diethylnitrosamine; D019426:Integrases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D012333:RNA, Messenger; D000099151:MAP Kinase Kinase Kinase 7; C498761:Tab2 protein, mouse; C045073:Cre recombinase