Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction
Abstract Background The autophagy adapter SQSTM1/p62 is crucial for maintaining homeostasis in various organs and cells due to its protein–protein interaction domains and involvement in diverse physiological and pathological processes. Vascular endothelium cells play a unique role in vascular biolog...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-02-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-04946-w |
| _version_ | 1797273500603383808 |
|---|---|
| author | Jing Feng Yan Li Yu Zhang Shengnan Sun Jian Sun Quanlin Xu Xingzhao Ji Yi Liu Qiang Wan |
| author_facet | Jing Feng Yan Li Yu Zhang Shengnan Sun Jian Sun Quanlin Xu Xingzhao Ji Yi Liu Qiang Wan |
| author_sort | Jing Feng |
| collection | DOAJ |
| description | Abstract Background The autophagy adapter SQSTM1/p62 is crucial for maintaining homeostasis in various organs and cells due to its protein–protein interaction domains and involvement in diverse physiological and pathological processes. Vascular endothelium cells play a unique role in vascular biology and contribute to vascular health. Methods Using the Cre-loxP system, we generated mice with endothelium cell-specific knockout of p62 mediated by Tek (Tek receptor tyrosine kinase)-cre to investigate the essential role of p62 in the endothelium. In vitro, we employed protein mass spectrometry and IPA to identify differentially expressed proteins upon knockdown of p62. Immunoprecipitation assays were conducted to demonstrate the interaction between p62 and FN1 or LAMC2 in human umbilical vein endothelium cells (HUVECs). Additionally, we identified the degradation pathway of FN1 and LAMC2 using the autophagy inhibitor 3-methyladenine (3-MA) or proteasome inhibitor MG132. Finally, the results of immunoprecipitation demonstrated that the interaction between p62 and LAMC2 was abolished in the PB1 truncation group of p62, while the interaction between p62 and FN1 was abolished in the UBA truncation group of p62. Results Our findings revealed that p62 Endo mice exhibited heart, lung, and kidney fibrosis compared to littermate controls, accompanied by severe cardiac dysfunction. Immunoprecipitation assays provided evidence of p62 acting as an autophagy adapter in the autophagy-lysosome pathway for FN1 and LAMC2 degradation respectively through PB1 and UBA domain with these proteins rather than proteasome system. Conclusions Our study demonstrates that defects in p62 within endothelium cells induce multi-organ fibrosis and cardiac dysfunction in mice. Our findings indicate that FN1 and LAMC2, as markers of (EndoMT), have detrimental effects on HUVECs and elucidate the autophagy-lysosome degradation mechanism of FN1 and LAMC2. |
| first_indexed | 2024-03-07T14:44:12Z |
| format | Article |
| id | doaj.art-f6181a889fb940d58565ec1a52d533a4 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-07T14:44:12Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-f6181a889fb940d58565ec1a52d533a42024-03-05T20:06:37ZengBMCJournal of Translational Medicine1479-58762024-02-0122111810.1186/s12967-024-04946-wEndothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunctionJing Feng0Yan Li1Yu Zhang2Shengnan Sun3Jian Sun4Quanlin Xu5Xingzhao Ji6Yi Liu7Qiang Wan8Key Laboratory of Cell Metabolism in Medical and Health of Shandong Provincial Health Commission, Jinan Central Hospital, Shandong UniversityDepartment of Pulmonary and Critical Care Medicine, The Second Hospital of Shandong UniversityDepartment of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital, Shandong UniversityKey Laboratory of Cell Metabolism in Medical and Health of Shandong Provincial Health Commission, Jinan Central Hospital, Shandong UniversityDepartment of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital, Shandong UniversityKey Laboratory of Cell Metabolism in Medical and Health of Shandong Provincial Health Commission, Jinan Central Hospital, Shandong UniversityAbstract Background The autophagy adapter SQSTM1/p62 is crucial for maintaining homeostasis in various organs and cells due to its protein–protein interaction domains and involvement in diverse physiological and pathological processes. Vascular endothelium cells play a unique role in vascular biology and contribute to vascular health. Methods Using the Cre-loxP system, we generated mice with endothelium cell-specific knockout of p62 mediated by Tek (Tek receptor tyrosine kinase)-cre to investigate the essential role of p62 in the endothelium. In vitro, we employed protein mass spectrometry and IPA to identify differentially expressed proteins upon knockdown of p62. Immunoprecipitation assays were conducted to demonstrate the interaction between p62 and FN1 or LAMC2 in human umbilical vein endothelium cells (HUVECs). Additionally, we identified the degradation pathway of FN1 and LAMC2 using the autophagy inhibitor 3-methyladenine (3-MA) or proteasome inhibitor MG132. Finally, the results of immunoprecipitation demonstrated that the interaction between p62 and LAMC2 was abolished in the PB1 truncation group of p62, while the interaction between p62 and FN1 was abolished in the UBA truncation group of p62. Results Our findings revealed that p62 Endo mice exhibited heart, lung, and kidney fibrosis compared to littermate controls, accompanied by severe cardiac dysfunction. Immunoprecipitation assays provided evidence of p62 acting as an autophagy adapter in the autophagy-lysosome pathway for FN1 and LAMC2 degradation respectively through PB1 and UBA domain with these proteins rather than proteasome system. Conclusions Our study demonstrates that defects in p62 within endothelium cells induce multi-organ fibrosis and cardiac dysfunction in mice. Our findings indicate that FN1 and LAMC2, as markers of (EndoMT), have detrimental effects on HUVECs and elucidate the autophagy-lysosome degradation mechanism of FN1 and LAMC2.https://doi.org/10.1186/s12967-024-04946-wSQSTM1/p62Endothelium cellsFibrosisCardiac dysfunctionFibronectin1Lamininγ2 |
| spellingShingle | Jing Feng Yan Li Yu Zhang Shengnan Sun Jian Sun Quanlin Xu Xingzhao Ji Yi Liu Qiang Wan Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction Journal of Translational Medicine SQSTM1/p62 Endothelium cells Fibrosis Cardiac dysfunction Fibronectin1 Lamininγ2 |
| title | Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction |
| title_full | Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction |
| title_fullStr | Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction |
| title_full_unstemmed | Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction |
| title_short | Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction |
| title_sort | endothelium specific deletion of p62 causes organ fibrosis and cardiac dysfunction |
| topic | SQSTM1/p62 Endothelium cells Fibrosis Cardiac dysfunction Fibronectin1 Lamininγ2 |
| url | https://doi.org/10.1186/s12967-024-04946-w |
| work_keys_str_mv | AT jingfeng endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT yanli endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT yuzhang endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT shengnansun endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT jiansun endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT quanlinxu endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT xingzhaoji endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT yiliu endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction AT qiangwan endotheliumspecificdeletionofp62causesorganfibrosisandcardiacdysfunction |