TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy
Abstract ULK1 is crucial for initiating autophagosome formation and its activity is tightly regulated by post-translational modifications and protein-protein interactions. In the present study, we demonstrate that TMEM189 (Transmembrane protein 189), also known as plasmanylethanolamine desaturase 1...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04722-y |
| _version_ | 1819061465544392704 |
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| author | Jiahong Yu Liujing Qu Yan Xia Xuan Zhang Jinqiu Feng Mengyuan Duan Pengli guo Yaxin Lou Ping Lv Wenping Lu Yingyu Chen |
| author_facet | Jiahong Yu Liujing Qu Yan Xia Xuan Zhang Jinqiu Feng Mengyuan Duan Pengli guo Yaxin Lou Ping Lv Wenping Lu Yingyu Chen |
| author_sort | Jiahong Yu |
| collection | DOAJ |
| description | Abstract ULK1 is crucial for initiating autophagosome formation and its activity is tightly regulated by post-translational modifications and protein-protein interactions. In the present study, we demonstrate that TMEM189 (Transmembrane protein 189), also known as plasmanylethanolamine desaturase 1 (PEDS1), negatively regulates the proteostasis of ULK1 and autophagy activity. In TMEM189-overexpressed cells, the formation of autophagesome is impaired, while TMEM189 knockdown increases cell autophagy. Further investigation reveals that TMEM189 interacts with and increases the instability of ULK1, as well as decreases its kinase activities. The TMEM189 N-terminal domain is required for the interaction with ULK1. Additionally, TMEM189 overexpression can disrupt the interaction between ULK1 and TRAF6, profoundly impairs K63-linked polyubiquitination of ULK1 and self-association, leading to the decrease of ULK1 stability. Moreover, in vitro and in vivo experiments suggest that TMEM189 deficiency results in the inhibition of tumorigenicity of gastric cancer. Our findings provide a new insight into the molecular regulation of autophagy and laboratory evidence for investigating the physiological and pathological roles of TMEM189. |
| first_indexed | 2024-12-21T14:43:19Z |
| format | Article |
| id | doaj.art-77dc6276345048008f7de839226a251b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-21T14:43:19Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-77dc6276345048008f7de839226a251b2022-12-21T19:00:07ZengNature Publishing GroupCell Death and Disease2041-48892022-04-0113411010.1038/s41419-022-04722-yTMEM189 negatively regulates the stability of ULK1 protein and cell autophagyJiahong Yu0Liujing Qu1Yan Xia2Xuan Zhang3Jinqiu Feng4Mengyuan Duan5Pengli guo6Yaxin Lou7Ping Lv8Wenping Lu9Yingyu Chen10Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityMedical and Healthy Analytical Center, Peking UniversityDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityDepartment of Hepatobiliary Surgery, First Medical Center, Chinese PLA General HospitalDepartment of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking UniversityAbstract ULK1 is crucial for initiating autophagosome formation and its activity is tightly regulated by post-translational modifications and protein-protein interactions. In the present study, we demonstrate that TMEM189 (Transmembrane protein 189), also known as plasmanylethanolamine desaturase 1 (PEDS1), negatively regulates the proteostasis of ULK1 and autophagy activity. In TMEM189-overexpressed cells, the formation of autophagesome is impaired, while TMEM189 knockdown increases cell autophagy. Further investigation reveals that TMEM189 interacts with and increases the instability of ULK1, as well as decreases its kinase activities. The TMEM189 N-terminal domain is required for the interaction with ULK1. Additionally, TMEM189 overexpression can disrupt the interaction between ULK1 and TRAF6, profoundly impairs K63-linked polyubiquitination of ULK1 and self-association, leading to the decrease of ULK1 stability. Moreover, in vitro and in vivo experiments suggest that TMEM189 deficiency results in the inhibition of tumorigenicity of gastric cancer. Our findings provide a new insight into the molecular regulation of autophagy and laboratory evidence for investigating the physiological and pathological roles of TMEM189.https://doi.org/10.1038/s41419-022-04722-y |
| spellingShingle | Jiahong Yu Liujing Qu Yan Xia Xuan Zhang Jinqiu Feng Mengyuan Duan Pengli guo Yaxin Lou Ping Lv Wenping Lu Yingyu Chen TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy Cell Death and Disease |
| title | TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy |
| title_full | TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy |
| title_fullStr | TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy |
| title_full_unstemmed | TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy |
| title_short | TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy |
| title_sort | tmem189 negatively regulates the stability of ulk1 protein and cell autophagy |
| url | https://doi.org/10.1038/s41419-022-04722-y |
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