Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy
Abstract Background A previous study found that MAF1 homolog, a negative regulator of RNA polymerase III (MAF1), protects the blood–brain barrier (BBB) in sepsis-associated encephalopathy (SAE); however, the related molecular mechanisms remain unclear. Subjects and methods In this study, a rat sepsi...
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BMC
2025-01-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00686-x |
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| author | Xuebiao Wei Wenqiang Jiang Zhonghua Wang Yichen Li Yuanwen Jing Yongli Han Linqiang Huang Shenglong Chen |
| author_facet | Xuebiao Wei Wenqiang Jiang Zhonghua Wang Yichen Li Yuanwen Jing Yongli Han Linqiang Huang Shenglong Chen |
| author_sort | Xuebiao Wei |
| collection | DOAJ |
| description | Abstract Background A previous study found that MAF1 homolog, a negative regulator of RNA polymerase III (MAF1), protects the blood–brain barrier (BBB) in sepsis-associated encephalopathy (SAE); however, the related molecular mechanisms remain unclear. Subjects and methods In this study, a rat sepsis model was constructed using the cecum ligation and puncture (CLP) method. In vitro, rat brain microvascular endothelial cells and astrocytes were stimulated with serum from the sepsis model rats. The loss of MAF1 protein levels and the molecular mechanisms leading to cell damage were investigated. Results It was shown in the SAE models that MAF1 was expressed at low levels. Knockdown of Cullin 2 (CUL2) stimulated the accumulation of MAF1 protein, attenuated the RNA sensor RIG-I/interferon regulatory factor 3 (IRF3) signaling pathway, and reduced cell apoptosis. Furthermore, it increased phosphatase and tensin homolog (PTEN) expression and inactivated the serine/threonine kinase (AKT)/mechanistic target of the rapamycin kinase (mTOR) signaling pathway. Interference with forkhead box O1 (FOXO1) inhibited MAF1 expression and activated the RIG-I/IRF3 signaling pathway, while MAF1 overexpression promoted PTEN expression, decreased cell apoptosis, and normalized autophagy. Conclusions These findings demonstrate that CUL2 promoted MAF1 ubiquitination and caused BBB injury in SAE. Through the regulatory loop of PTEN/AKT/FOXO1/MAF1, CUL2 initiated the gradual downregulation of MAF1, which subsequently regulated polymerase III (Pol III)-dependent transcription and played essential roles in cell apoptosis in SAE. Clinical trial number: not applicable. Graphical Abstract |
| format | Article |
| id | doaj-art-1ed3c15c693e40e0910338d2bccfe0b8 |
| institution | Kabale University |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-1ed3c15c693e40e0910338d2bccfe0b82025-01-26T12:42:54ZengBMCCellular & Molecular Biology Letters1689-13922025-01-0130112410.1186/s11658-025-00686-xFeedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathyXuebiao Wei0Wenqiang Jiang1Zhonghua Wang2Yichen Li3Yuanwen Jing4Yongli Han5Linqiang Huang6Shenglong Chen7Department of Geriatric Intensive Medicine, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Geriatric Intensive Medicine, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityAbstract Background A previous study found that MAF1 homolog, a negative regulator of RNA polymerase III (MAF1), protects the blood–brain barrier (BBB) in sepsis-associated encephalopathy (SAE); however, the related molecular mechanisms remain unclear. Subjects and methods In this study, a rat sepsis model was constructed using the cecum ligation and puncture (CLP) method. In vitro, rat brain microvascular endothelial cells and astrocytes were stimulated with serum from the sepsis model rats. The loss of MAF1 protein levels and the molecular mechanisms leading to cell damage were investigated. Results It was shown in the SAE models that MAF1 was expressed at low levels. Knockdown of Cullin 2 (CUL2) stimulated the accumulation of MAF1 protein, attenuated the RNA sensor RIG-I/interferon regulatory factor 3 (IRF3) signaling pathway, and reduced cell apoptosis. Furthermore, it increased phosphatase and tensin homolog (PTEN) expression and inactivated the serine/threonine kinase (AKT)/mechanistic target of the rapamycin kinase (mTOR) signaling pathway. Interference with forkhead box O1 (FOXO1) inhibited MAF1 expression and activated the RIG-I/IRF3 signaling pathway, while MAF1 overexpression promoted PTEN expression, decreased cell apoptosis, and normalized autophagy. Conclusions These findings demonstrate that CUL2 promoted MAF1 ubiquitination and caused BBB injury in SAE. Through the regulatory loop of PTEN/AKT/FOXO1/MAF1, CUL2 initiated the gradual downregulation of MAF1, which subsequently regulated polymerase III (Pol III)-dependent transcription and played essential roles in cell apoptosis in SAE. Clinical trial number: not applicable. Graphical Abstracthttps://doi.org/10.1186/s11658-025-00686-xSepsisBlood–brain barrierMAF1UbiquitinationApoptosis |
| spellingShingle | Xuebiao Wei Wenqiang Jiang Zhonghua Wang Yichen Li Yuanwen Jing Yongli Han Linqiang Huang Shenglong Chen Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy Cellular & Molecular Biology Letters Sepsis Blood–brain barrier MAF1 Ubiquitination Apoptosis |
| title | Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy |
| title_full | Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy |
| title_fullStr | Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy |
| title_full_unstemmed | Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy |
| title_short | Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy |
| title_sort | feedback loop centered on maf1 reduces blood brain barrier damage in sepsis associated encephalopathy |
| topic | Sepsis Blood–brain barrier MAF1 Ubiquitination Apoptosis |
| url | https://doi.org/10.1186/s11658-025-00686-x |
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