p38MAPK guards the integrity of endosomal compartments through regulating necrotic death
Abstract Pathogens trigger activation of sensors of the innate immune system that initiate molecular signaling enabling appropriate host defense programs. Although recognition of pathogen-specific moieties or PAMPs by specialized receptors of the immune system is well defined for a great number of p...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-20786-4 |
| _version_ | 1828222510506704896 |
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| author | Jia Yao Svetlana Atasheva Randall Toy Emmeline L. Blanchard Philip J. Santangelo Krishnendu Roy Edward S. Mocarski Dmitry M. Shayakhmetov |
| author_facet | Jia Yao Svetlana Atasheva Randall Toy Emmeline L. Blanchard Philip J. Santangelo Krishnendu Roy Edward S. Mocarski Dmitry M. Shayakhmetov |
| author_sort | Jia Yao |
| collection | DOAJ |
| description | Abstract Pathogens trigger activation of sensors of the innate immune system that initiate molecular signaling enabling appropriate host defense programs. Although recognition of pathogen-specific moieties or PAMPs by specialized receptors of the immune system is well defined for a great number of pathogens, the mechanisms of sensing of pathogen-induced functional perturbations to the host cell remain poorly understood. Here we show that the disruption of endosomal compartments in macrophages by a bacterium or fully synthetic nanoparticles activates stress-response p38MAPK kinase, which triggers execution of cell death of a necrotic type. p38MAPK-mediated necrosis occurs in cells with a compound homozygous deletion of pyroptosis-inducing caspases-1 and -11, apoptotic caspase-8, and necroptosis-inducing receptor-interacting protein kinase-3 (RIPK3), indicating that all of these principal cell death mediators are dispensable for p38MAPK-induced necrosis in response to endosome rupture. p38MAPK-mediated necrosis is suppressed by the receptor-interacting protein kinase 1, RIPK1, and degradation of RIPK1 sensitizes macrophages to necrotic death. Since pathogen-induced cell death of necrotic types is implicated in host defense against infection, our results indicate that functional perturbations in host cells are sensed as a component of the innate immune system. |
| first_indexed | 2024-04-12T16:55:50Z |
| format | Article |
| id | doaj.art-82c6fbda93044ded80e53e06e8ddf1db |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T16:55:50Z |
| publishDate | 2022-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-82c6fbda93044ded80e53e06e8ddf1db2022-12-22T03:24:15ZengNature PortfolioScientific Reports2045-23222022-09-0112111510.1038/s41598-022-20786-4p38MAPK guards the integrity of endosomal compartments through regulating necrotic deathJia Yao0Svetlana Atasheva1Randall Toy2Emmeline L. Blanchard3Philip J. Santangelo4Krishnendu Roy5Edward S. Mocarski6Dmitry M. Shayakhmetov7Departments of Pediatrics and Medicine, Lowance Center for Human Immunology, Emory University School of MedicineDepartments of Pediatrics and Medicine, Lowance Center for Human Immunology, Emory University School of MedicineWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory UniversityWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory UniversityWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory UniversityWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory UniversityDepartment of Microbiology and Immunology, Emory University School of MedicineDepartments of Pediatrics and Medicine, Lowance Center for Human Immunology, Emory University School of MedicineAbstract Pathogens trigger activation of sensors of the innate immune system that initiate molecular signaling enabling appropriate host defense programs. Although recognition of pathogen-specific moieties or PAMPs by specialized receptors of the immune system is well defined for a great number of pathogens, the mechanisms of sensing of pathogen-induced functional perturbations to the host cell remain poorly understood. Here we show that the disruption of endosomal compartments in macrophages by a bacterium or fully synthetic nanoparticles activates stress-response p38MAPK kinase, which triggers execution of cell death of a necrotic type. p38MAPK-mediated necrosis occurs in cells with a compound homozygous deletion of pyroptosis-inducing caspases-1 and -11, apoptotic caspase-8, and necroptosis-inducing receptor-interacting protein kinase-3 (RIPK3), indicating that all of these principal cell death mediators are dispensable for p38MAPK-induced necrosis in response to endosome rupture. p38MAPK-mediated necrosis is suppressed by the receptor-interacting protein kinase 1, RIPK1, and degradation of RIPK1 sensitizes macrophages to necrotic death. Since pathogen-induced cell death of necrotic types is implicated in host defense against infection, our results indicate that functional perturbations in host cells are sensed as a component of the innate immune system.https://doi.org/10.1038/s41598-022-20786-4 |
| spellingShingle | Jia Yao Svetlana Atasheva Randall Toy Emmeline L. Blanchard Philip J. Santangelo Krishnendu Roy Edward S. Mocarski Dmitry M. Shayakhmetov p38MAPK guards the integrity of endosomal compartments through regulating necrotic death Scientific Reports |
| title | p38MAPK guards the integrity of endosomal compartments through regulating necrotic death |
| title_full | p38MAPK guards the integrity of endosomal compartments through regulating necrotic death |
| title_fullStr | p38MAPK guards the integrity of endosomal compartments through regulating necrotic death |
| title_full_unstemmed | p38MAPK guards the integrity of endosomal compartments through regulating necrotic death |
| title_short | p38MAPK guards the integrity of endosomal compartments through regulating necrotic death |
| title_sort | p38mapk guards the integrity of endosomal compartments through regulating necrotic death |
| url | https://doi.org/10.1038/s41598-022-20786-4 |
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