2. Academic Validation
  3. MGST3 regulates BACE1 protein translation and amyloidogenesis by controlling the RGS4-mediated AKT signaling pathway

MGST3 regulates BACE1 protein translation and amyloidogenesis by controlling the RGS4-mediated AKT signaling pathway

  • J Biol Chem. 2024 Jul 4;300(8):107530. doi: 10.1016/j.jbc.2024.107530.
Yalan Pu 1,  Jie Yang 2,  Qiuling Pan 3,  Chenlu Li 3,  Lu Wang 3,  Xiaoyong Xie 3,  Xue Chen 3,  Fei Xiao 4,  Guojun Chen 5
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China; Department of Neurology, Langzhong People's Hospital, Nanchong, Sichuan, China.
  • 2 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China; Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of TCM, Sichuan, China.
  • 3 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
  • 4 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China. Electronic address: feixiao81@126.com.
  • 5 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China. Electronic address: GJChen@hospital.cqmu.edu.cn.
PMID: 38971310 DOI: 10.1016/j.jbc.2024.107530
Abstract

Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and Apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer's disease. Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving Enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular Reactive Oxygen Species level but selectively reduced the expression of Apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes, the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysteinyl leukotrienes but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to Akt activity, as the protein level of phosphorylated Akt was significantly reduced by silencing of MGST3 and RGS4, and the Akt Inhibitor abolished the effect of MGST3/RGS4 on phosphorylated Akt and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream Akt signaling pathway.

Keywords

AKT; Alzheimer’s disease; BACE1; MGST3; RGS4; translation.

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