2. Academic Validation
  3. NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma

NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma

  • Cell Death Dis. 2022 Mar 2;13(3):197. doi: 10.1038/s41419-022-04629-8.
Xi Huang  # 1,  Wen Cao  # 1,  Shunnan Yao 1,  Jing Chen 1,  Yang Liu 1,  Jianwei Qu 1,  Yi Li 1,  Xiaoyan Han 1,  Jingsong He 1,  He Huang 1 2,  Enfan Zhang 3,  Zhen Cai 4 5
Affiliations

Affiliations

  • 1 Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Institute of Hematology, Zhejiang University, Hangzhou, China.
  • 3 Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. efzhang@zju.edu.cn.
  • 4 Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. caiz@zju.edu.cn.
  • 5 Institute of Hematology, Zhejiang University, Hangzhou, China. caiz@zju.edu.cn.
  • # Contributed equally.
PMID: 35236820 DOI: 10.1038/s41419-022-04629-8
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.

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