TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria
Abstract Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is a central mediator of intracellular host defense signaling promoting inflammatory gene expression. Hence, TAK1 is a prime target of intracellular bacterial effectors in blocking inflammatory responses. However, whe...
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| Format: | Article |
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07760-4 |
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| author | Wilfred López-Pérez Roland E. González-Calderón Kazuhito Sai Prashant Rai Jacqueline M. MacStudy Yosuke Sakamachi Cameron Parsons Sophia Kathariou Michael B. Fessler Jun Ninomiya-Tsuji |
| author_facet | Wilfred López-Pérez Roland E. González-Calderón Kazuhito Sai Prashant Rai Jacqueline M. MacStudy Yosuke Sakamachi Cameron Parsons Sophia Kathariou Michael B. Fessler Jun Ninomiya-Tsuji |
| author_sort | Wilfred López-Pérez |
| collection | DOAJ |
| description | Abstract Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is a central mediator of intracellular host defense signaling promoting inflammatory gene expression. Hence, TAK1 is a prime target of intracellular bacterial effectors in blocking inflammatory responses. However, when TAK1 is inhibited, host cells alternatively activate multiple cell death pathways, namely caspase 8-dependent apoptosis and pyroptosis, and receptor interacting protein kinase 3 (RIPK3)-dependent necroptosis. While these pathways ultimately lead to cell death, we found that they also modulate mitochondria to produce mitochondrial reactive oxygen species (ROS). Although as cell death executors, mixed lineage kinase-like (MLKL) and gasdermins are known to form pores in the plasma membrane, we found that TAK1 inhibition translocates them to mitochondria resulting in elevated mitochondrial ROS. Ablation of both MLKL and gasdermins diminished TAK1 inhibition-induced elevation of ROS and exacerbated intracellular bacterial colonization. Our results reveal that these cell death pathways have an alternative host defense role to prevent intracellular pathogen colonization. |
| format | Article |
| id | doaj-art-bc99dc625cff4f6fb5712c8e2f32033d |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-bc99dc625cff4f6fb5712c8e2f32033d2025-08-20T03:22:57ZengNature Publishing GroupCell Death and Disease2041-48892025-06-0116111010.1038/s41419-025-07760-4TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondriaWilfred López-Pérez0Roland E. González-Calderón1Kazuhito Sai2Prashant Rai3Jacqueline M. MacStudy4Yosuke Sakamachi5Cameron Parsons6Sophia Kathariou7Michael B. Fessler8Jun Ninomiya-Tsuji9Department of Biological Sciences and Toxicology Program, North Carolina State UniversityDepartment of Biological Sciences and Toxicology Program, North Carolina State UniversityDepartment of Biological Sciences and Toxicology Program, North Carolina State UniversityImmunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institute of HealthDepartment of Biological Sciences and Toxicology Program, North Carolina State UniversityDepartment of Biological Sciences and Toxicology Program, North Carolina State UniversityDepartment of Food, Bioprocessing, and Nutrition Sciences, North Carolina State UniversityDepartment of Food, Bioprocessing, and Nutrition Sciences, North Carolina State UniversityImmunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institute of HealthDepartment of Biological Sciences and Toxicology Program, North Carolina State UniversityAbstract Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is a central mediator of intracellular host defense signaling promoting inflammatory gene expression. Hence, TAK1 is a prime target of intracellular bacterial effectors in blocking inflammatory responses. However, when TAK1 is inhibited, host cells alternatively activate multiple cell death pathways, namely caspase 8-dependent apoptosis and pyroptosis, and receptor interacting protein kinase 3 (RIPK3)-dependent necroptosis. While these pathways ultimately lead to cell death, we found that they also modulate mitochondria to produce mitochondrial reactive oxygen species (ROS). Although as cell death executors, mixed lineage kinase-like (MLKL) and gasdermins are known to form pores in the plasma membrane, we found that TAK1 inhibition translocates them to mitochondria resulting in elevated mitochondrial ROS. Ablation of both MLKL and gasdermins diminished TAK1 inhibition-induced elevation of ROS and exacerbated intracellular bacterial colonization. Our results reveal that these cell death pathways have an alternative host defense role to prevent intracellular pathogen colonization.https://doi.org/10.1038/s41419-025-07760-4 |
| spellingShingle | Wilfred López-Pérez Roland E. González-Calderón Kazuhito Sai Prashant Rai Jacqueline M. MacStudy Yosuke Sakamachi Cameron Parsons Sophia Kathariou Michael B. Fessler Jun Ninomiya-Tsuji TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria Cell Death and Disease |
| title | TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria |
| title_full | TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria |
| title_fullStr | TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria |
| title_full_unstemmed | TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria |
| title_short | TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria |
| title_sort | tak1 inhibition activates pore forming proteins to block intracellular bacterial growth through modulating mitochondria |
| url | https://doi.org/10.1038/s41419-025-07760-4 |
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