TAK1 inhibition elicits mitochondrial ROS to block intracellular bacterial colonization
Autor: | Kazuhito Sai, Yosuke Sakamachi, Sophia Kathariou, Jun Ninomiya-Tsuji, Cameron Parsons, Wilfred Lopez‐Perez |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Mitochondrial ROS Colony Count Microbial Intracellular Space Host Defense Mechanism MAP3K7 Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Salmonella Genetics Animals Hydrogen Sulfide Protein kinase A Molecular Biology Multidisciplinary Bacteria Caspase 3 Chemistry Effector Intracellular parasite Biological Sciences MAP Kinase Kinase Kinases Yersinia Mitochondria Cell biology 030104 developmental biology Receptor-Interacting Protein Serine-Threonine Kinases 030220 oncology & carcinogenesis Reactive Oxygen Species Bacterial outer membrane Intracellular Biotechnology |
Zdroj: | Proc Natl Acad Sci U S A |
ISSN: | 1091-6490 0027-8424 |
Popis: | Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is an intracellular signaling intermediate of inflammatory responses. However, a series of mouse Tak1 gene deletion analyses have revealed that ablation of TAK1 does not prevent but rather elicits inflammation, which is accompanied by elevation of reactive oxygen species (ROS). This has been considered a consequence of impaired TAK1-dependent maintenance of tissue integrity. Contrary to this view, here we propose that TAK1 inhibition-induced ROS are an active cellular process that targets intracellular bacteria. Intracellular bacterial effector proteins such as Yersinia's outer membrane protein YopJ are known to inhibit TAK1 to circumvent the inflammatory host responses. We found that such TAK1 inhibition induces mitochondrial-derived ROS, which effectively destroys intracellular bacteria. Two cell death-signaling molecules, caspase 8 and RIPK3, cooperatively participate in TAK1 inhibition-induced ROS and blockade of intracellular bacterial growth. Our results reveal a previously unrecognized host defense mechanism, which is initiated by host recognition of pathogen-induced impairment in a host protein, TAK1, but not directly of pathogens. |
Databáze: | OpenAIRE |
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