Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis
Abstract Pasteurella multocida is an opportunistic zoonotic pathogen that primarily causes fatal respiratory diseases, such as pneumonia and respiratory syndromes. However, the precise mechanistic understanding of how P. multocida disrupts the epithelial barrier in mammalian lung remains largely unk...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Veterinary Research |
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| Online Access: | https://doi.org/10.1186/s13567-024-01285-y |
| _version_ | 1797259103283707904 |
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| author | Guangfu Zhao Yunhan Tang Xiongli Liu Pan Li Tianci Zhang Nengzhang Li Fang He Yuanyi Peng |
| author_facet | Guangfu Zhao Yunhan Tang Xiongli Liu Pan Li Tianci Zhang Nengzhang Li Fang He Yuanyi Peng |
| author_sort | Guangfu Zhao |
| collection | DOAJ |
| description | Abstract Pasteurella multocida is an opportunistic zoonotic pathogen that primarily causes fatal respiratory diseases, such as pneumonia and respiratory syndromes. However, the precise mechanistic understanding of how P. multocida disrupts the epithelial barrier in mammalian lung remains largely unknown. In this study, using unbiased RNA-seq analysis, we found that the evolutionarily conserved Hippo-Yap pathway was dysregulated after P. multocida infection. Given the complexity of P. multocida infection associated with lung injury and systemic inflammatory processes, we employed a combination of cell culture models, mouse models, and rabbit models to investigate the dynamics of the Hippo-Yap pathway during P. multocida infection. Our findings reveal that P. multocida infection activates the Hippo-Yap pathway both in vitro and in vivo, by upregulating the upstream factors p-Mst1/2, p-Lats1, and p-Yap, and downregulating the downstream effectors Birc5, Cyr61, and Slug. Conversely, pharmacological inhibition of the Hippo pathway by XMU-MP-1 significantly rescued pulmonary epithelial cell apoptosis in vitro and reduced lung injury, systemic inflammation, and mouse mortality in vivo. Mechanistic studies revealed that P. multocida induced up-regulation of Rassf1 expression, and Rassf1 enhanced Hippo-Yap pathway through phosphorylation. Accordingly, in vitro knockdown of Rassf1 significantly enhanced Yap activity and expression of Yap downstream factors and reduced apoptosis during P. multocida infection. P. multocida-infected rabbit samples also showed overexpression of Rassf1, p-Lats1, and p-Yap, suggesting that P. multocida activates the Rassf1-Hippo-Yap pathway. These results elucidate the pathogenic role of the Rassf1-Hippo-Yap pathway in P. multocida infection and suggest that this pathway has the potential to be a drug target for the treatment of pasteurellosis. |
| first_indexed | 2024-04-24T23:04:06Z |
| format | Article |
| id | doaj.art-c154eb9998134387adb9243b8a7fe335 |
| institution | Directory Open Access Journal |
| issn | 1297-9716 |
| language | English |
| last_indexed | 2024-04-24T23:04:06Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Veterinary Research |
| spelling | doaj.art-c154eb9998134387adb9243b8a7fe3352024-03-17T12:35:11ZengBMCVeterinary Research1297-97162024-03-0155111310.1186/s13567-024-01285-yPasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosisGuangfu Zhao0Yunhan Tang1Xiongli Liu2Pan Li3Tianci Zhang4Nengzhang Li5Fang He6Yuanyi Peng7College of Veterinary Medicine, Southwest UniversityCollege of Veterinary Medicine, Southwest UniversityCollege of Veterinary Medicine, Southwest UniversityDepartment of Environment and Safety Engineering, Taiyuan Institute of TechnologyDepartment of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan UniversityCollege of Veterinary Medicine, Southwest UniversityCollege of Veterinary Medicine, Southwest UniversityCollege of Veterinary Medicine, Southwest UniversityAbstract Pasteurella multocida is an opportunistic zoonotic pathogen that primarily causes fatal respiratory diseases, such as pneumonia and respiratory syndromes. However, the precise mechanistic understanding of how P. multocida disrupts the epithelial barrier in mammalian lung remains largely unknown. In this study, using unbiased RNA-seq analysis, we found that the evolutionarily conserved Hippo-Yap pathway was dysregulated after P. multocida infection. Given the complexity of P. multocida infection associated with lung injury and systemic inflammatory processes, we employed a combination of cell culture models, mouse models, and rabbit models to investigate the dynamics of the Hippo-Yap pathway during P. multocida infection. Our findings reveal that P. multocida infection activates the Hippo-Yap pathway both in vitro and in vivo, by upregulating the upstream factors p-Mst1/2, p-Lats1, and p-Yap, and downregulating the downstream effectors Birc5, Cyr61, and Slug. Conversely, pharmacological inhibition of the Hippo pathway by XMU-MP-1 significantly rescued pulmonary epithelial cell apoptosis in vitro and reduced lung injury, systemic inflammation, and mouse mortality in vivo. Mechanistic studies revealed that P. multocida induced up-regulation of Rassf1 expression, and Rassf1 enhanced Hippo-Yap pathway through phosphorylation. Accordingly, in vitro knockdown of Rassf1 significantly enhanced Yap activity and expression of Yap downstream factors and reduced apoptosis during P. multocida infection. P. multocida-infected rabbit samples also showed overexpression of Rassf1, p-Lats1, and p-Yap, suggesting that P. multocida activates the Rassf1-Hippo-Yap pathway. These results elucidate the pathogenic role of the Rassf1-Hippo-Yap pathway in P. multocida infection and suggest that this pathway has the potential to be a drug target for the treatment of pasteurellosis.https://doi.org/10.1186/s13567-024-01285-yPasteurella multocidapulmonary epitheliumRassf1-Hippo-Yap pathwayapoptosispathogenesis |
| spellingShingle | Guangfu Zhao Yunhan Tang Xiongli Liu Pan Li Tianci Zhang Nengzhang Li Fang He Yuanyi Peng Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis Veterinary Research Pasteurella multocida pulmonary epithelium Rassf1-Hippo-Yap pathway apoptosis pathogenesis |
| title | Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis |
| title_full | Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis |
| title_fullStr | Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis |
| title_full_unstemmed | Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis |
| title_short | Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis |
| title_sort | pasteurella multocida activates rassf1 hippo yap pathway to induce pulmonary epithelial apoptosis |
| topic | Pasteurella multocida pulmonary epithelium Rassf1-Hippo-Yap pathway apoptosis pathogenesis |
| url | https://doi.org/10.1186/s13567-024-01285-y |
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