NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma
Abstract Multiple myeloma (MM) remains an incurable plasma cell cancer characterized by abnormal secretion of monoclonal immunoglobulins. The molecular mechanism that regulates the drug sensitivity of MM cells is being intensively studied. Here, we report an unexpected finding that the protein encod...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04629-8 |
| _version_ | 1818919685516689408 |
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| author | Xi Huang Wen Cao Shunnan Yao Jing Chen Yang Liu Jianwei Qu Yi Li Xiaoyan Han Jingsong He He Huang Enfan Zhang Zhen Cai |
| author_facet | Xi Huang Wen Cao Shunnan Yao Jing Chen Yang Liu Jianwei Qu Yi Li Xiaoyan Han Jingsong He He Huang Enfan Zhang Zhen Cai |
| author_sort | Xi Huang |
| collection | DOAJ |
| description | Abstract Multiple myeloma (MM) remains an incurable plasma cell cancer characterized by abnormal secretion of monoclonal immunoglobulins. The molecular mechanism that regulates the drug sensitivity of MM cells is being intensively studied. Here, we report an unexpected finding that the protein encoded by neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L), which is a HECT E3 ligase, binds the 19S proteasome, limiting its proteolytic function and enhancing autophagy. Suppression of NEDD4L expression reduced bortezomib (Bor) sensitivity in vitro and in vivo, mainly through autophagy inhibition mediated by low NEDD4L expression, which was rescued by an autophagy activator. Clinically, elevated expression of NEDD4L is associated with a considerably increased probability of responding to Bor, a prolonged response duration, and improved overall prognosis, supporting both the use of NEDD4L as a biomarker to identify patients most likely to benefit from Bor and the regulation of NEDD4L as a new approach in myeloma therapy. |
| first_indexed | 2024-12-20T01:09:47Z |
| format | Article |
| id | doaj.art-ecd6f5cc86e54cb79176915776c694b1 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-20T01:09:47Z |
| publishDate | 2022-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-ecd6f5cc86e54cb79176915776c694b12022-12-21T19:58:44ZengNature Publishing GroupCell Death and Disease2041-48892022-03-0113311210.1038/s41419-022-04629-8NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myelomaXi Huang0Wen Cao1Shunnan Yao2Jing Chen3Yang Liu4Jianwei Qu5Yi Li6Xiaoyan Han7Jingsong He8He Huang9Enfan Zhang10Zhen Cai11Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityBone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityAbstract Multiple myeloma (MM) remains an incurable plasma cell cancer characterized by abnormal secretion of monoclonal immunoglobulins. The molecular mechanism that regulates the drug sensitivity of MM cells is being intensively studied. Here, we report an unexpected finding that the protein encoded by neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L), which is a HECT E3 ligase, binds the 19S proteasome, limiting its proteolytic function and enhancing autophagy. Suppression of NEDD4L expression reduced bortezomib (Bor) sensitivity in vitro and in vivo, mainly through autophagy inhibition mediated by low NEDD4L expression, which was rescued by an autophagy activator. Clinically, elevated expression of NEDD4L is associated with a considerably increased probability of responding to Bor, a prolonged response duration, and improved overall prognosis, supporting both the use of NEDD4L as a biomarker to identify patients most likely to benefit from Bor and the regulation of NEDD4L as a new approach in myeloma therapy.https://doi.org/10.1038/s41419-022-04629-8 |
| spellingShingle | Xi Huang Wen Cao Shunnan Yao Jing Chen Yang Liu Jianwei Qu Yi Li Xiaoyan Han Jingsong He He Huang Enfan Zhang Zhen Cai NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma Cell Death and Disease |
| title | NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma |
| title_full | NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma |
| title_fullStr | NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma |
| title_full_unstemmed | NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma |
| title_short | NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma |
| title_sort | nedd4l binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma |
| url | https://doi.org/10.1038/s41419-022-04629-8 |
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