2. Academic Validation
  3. CaMKII suppresses proteotoxicity by phosphorylating BAG3 in response to proteasomal dysfunction

CaMKII suppresses proteotoxicity by phosphorylating BAG3 in response to proteasomal dysfunction

  • EMBO Rep. 2024 Oct;25(10):4488-4514. doi: 10.1038/s44319-024-00248-w.
Chenliang Zhang # 1,  Huanji Xu # 2,  Qiulin Tang 1,  Yichun Duan 2,  Hongwei Xia 1,  Huixi Huang 1,  Di Ye 2,  Feng Bi 3 4
Affiliations

Affiliations

  • 1 Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 2 Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 3 Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. bifeng@scu.edu.cn.
  • 4 Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. bifeng@scu.edu.cn.
  • # Contributed equally.
PMID: 39261742 DOI: 10.1038/s44319-024-00248-w
Abstract

Protein quality control serves as the primary defense mechanism for cells against proteotoxicity induced by Proteasome dysfunction. While cells can limit the build-up of ubiquitinated misfolded proteins during Proteasome inhibition, the precise mechanism is unclear. Here, we find that protein kinase CA2+/Calmodulin (CaM)-dependent protein kinase II (CaMKII) maintains proteostasis during Proteasome inhibition. We show that Proteasome inhibition activates CaMKII, which phosphorylates B-cell lymphoma 2 (Bcl-2)-associated athanogene 3 (BAG3) at residues S173, S377, and S386. Phosphorylated BAG3 activates the heme-regulated inhibitor (HRI)- eukaryotic initiation factor-2α (eIF2α) signaling pathway, suppressing protein synthesis and the production of aggregated ubiquitinated misfolded proteins, ultimately mitigating the proteotoxic crisis. Inhibition of CaMKII exacerbates the accumulation of aggregated misfolded proteins and Paraptosis induced by Proteasome inhibitors. Based on these findings, we validate that combined targeting of Proteasome and CaMKII accelerates tumor cell death and enhances the efficacy of Proteasome inhibitors in tumor treatment. Our data unveil a new proteasomal inhibition-induced misfolded protein quality control mechanism and propose a novel therapeutic intervention for Proteasome inhibitor-mediated tumor treatment.

Keywords

BAG3; CaMKII; HRI; Paraptosis; Proteasome Inhibition.

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