Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries
Abstract Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04796-y |
| _version_ | 1797388119150952448 |
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| author | Qing Fang Guoqing Jing Ying Zhang Hongyu Wang Huan Luo Yun Xia Qiyan Jin Yuping Liu Jing Zuo Cheng Yang Xiaodong Zhang Shi Liu Xiaojing Wu Xuemin Song |
| author_facet | Qing Fang Guoqing Jing Ying Zhang Hongyu Wang Huan Luo Yun Xia Qiyan Jin Yuping Liu Jing Zuo Cheng Yang Xiaodong Zhang Shi Liu Xiaojing Wu Xuemin Song |
| author_sort | Qing Fang |
| collection | DOAJ |
| description | Abstract Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391–964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1–247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway. |
| first_indexed | 2024-03-08T22:35:08Z |
| format | Article |
| id | doaj.art-36d000813a0a439ea30d94045967163b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-08T22:35:08Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-36d000813a0a439ea30d94045967163b2023-12-17T12:28:41ZengBMCJournal of Translational Medicine1479-58762023-12-0121111610.1186/s12967-023-04796-yErbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuriesQing Fang0Guoqing Jing1Ying Zhang2Hongyu Wang3Huan Luo4Yun Xia5Qiyan Jin6Yuping Liu7Jing Zuo8Cheng Yang9Xiaodong Zhang10Shi Liu11Xiaojing Wu12Xuemin Song13The Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityCollege of Life Sciences at, Wuhan UniversityCollege of Life Sciences at, Wuhan UniversityDepartment of Anesthesiology, Renmin Hospital of Wuhan UniversityThe Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityAbstract Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391–964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1–247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway.https://doi.org/10.1186/s12967-023-04796-yErbinAutophagyLysosomeTFEBSepsis |
| spellingShingle | Qing Fang Guoqing Jing Ying Zhang Hongyu Wang Huan Luo Yun Xia Qiyan Jin Yuping Liu Jing Zuo Cheng Yang Xiaodong Zhang Shi Liu Xiaojing Wu Xuemin Song Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries Journal of Translational Medicine Erbin Autophagy Lysosome TFEB Sepsis |
| title | Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries |
| title_full | Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries |
| title_fullStr | Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries |
| title_full_unstemmed | Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries |
| title_short | Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries |
| title_sort | erbin accelerates tfeb mediated lysosome biogenesis and autophagy and alleviates sepsis induced inflammatory responses and organ injuries |
| topic | Erbin Autophagy Lysosome TFEB Sepsis |
| url | https://doi.org/10.1186/s12967-023-04796-y |
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