@article{lopez-perez_sai_sakamachi_parsons_kathariou_ninomiya-tsuji_2021, title={TAK1 inhibition elicits mitochondrial ROS to block intracellular bacterial colonization}, volume={118}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.2023647118}, abstractNote={Significance We have found that bacterial inhibition of host TAK1 inflammatory signaling elicits an alternative host defense mechanism involving production of mitochondrial reactive oxygen species through caspase 8 and RIPK3. This finding allows a reinterpretation of mouse phenotypes harboring tissue-specific gene deletion of Tak1, many of which die from tissue damage previously ascribed to impaired TAK1-dependent tissue homeostasis. We suggest that these phenotypes arise from misrecognition of compromised TAK1 as pathogen invasion. 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.}, number={25}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Lopez-Perez, Wilfred and Sai, Kazuhito and Sakamachi, Yosuke and Parsons, Cameron and Kathariou, Sophia and Ninomiya-Tsuji, Jun}, year={2021}, month={Jun} }