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  3. JNK/Itch Axis Mediates the Lipopolysaccharide-Induced Ubiquitin-Proteasome-Dependent Degradation of Ferritin Light Chain in Murine Macrophage Cells

JNK/Itch Axis Mediates the Lipopolysaccharide-Induced Ubiquitin-Proteasome-Dependent Degradation of Ferritin Light Chain in Murine Macrophage Cells

  • Inflammation. 2022 Jun;45(3):1089-1100. doi: 10.1007/s10753-021-01603-y.
Shufen He  # 1,  Jianqi Xue 1,  Pengxiu Cao  # 1,  Jianyuan Hou 1,  Yan Cui 1,  Jing Chang 1,  Liying Huang 1,  Yu Han 1,  Xianglin Duan 1,  Ke Tan 2 3 4,  Yumei Fan 5 6 7
Affiliations

Affiliations

  • 1 Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Hebei Province, Shijiazhuang, 050024, PR China.
  • 2 Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Hebei Province, Shijiazhuang, 050024, PR China. tanke@hebtu.edu.cn.
  • 3 Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang, 050024, PR China. tanke@hebtu.edu.cn.
  • 4 Ministry of Education Key Laboratory of Molecular and Cellular Biology, College of Life Science, Hebei Normal University, Shijiazhuang, 050024, PR China. tanke@hebtu.edu.cn.
  • 5 Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Hebei Province, Shijiazhuang, 050024, PR China. fanyumei@hebtu.edu.cn.
  • 6 Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang, 050024, PR China. fanyumei@hebtu.edu.cn.
  • 7 Ministry of Education Key Laboratory of Molecular and Cellular Biology, College of Life Science, Hebei Normal University, Shijiazhuang, 050024, PR China. fanyumei@hebtu.edu.cn.
  • # Contributed equally.
PMID: 34837126 DOI: 10.1007/s10753-021-01603-y
Abstract

Ferritin, which is composed of a heavy chain and a light chain, plays a critical role in maintaining iron homeostasis by sequestering iron. The ferritin light chain (FTL) is responsible for the stability of the ferritin complex. We have previously shown that overexpression of FTL decreases the levels of the labile iron pool (LIP) and Reactive Oxygen Species (ROS) in lipopolysaccharide (LPS)-treated murine macrophage cells. The protein level of FTL was downregulated by LPS within a short treatment period. However, the mechanism underlying the LPS-induced changes in the FTL levels is not known. In the present study, we report that LPS induces the ubiquitin-proteasome-dependent degradation of FTL and that the mechanism of LPS-induced FTL degradation involves the JNK/Itch axis. We found that LPS downregulates the protein and mRNA levels of FTL in a time-dependent manner. The Proteasome Inhibitor MG-132 significantly reverses the LPS-induced decrease in FTL. Furthermore, we observed that LPS treatment cannot cause ubiquitination of the lysine site (K105 and K144) mutant of FTL. Interestingly, LPS-mediated ubiquitin-dependent degradation of FTL is significantly inhibited by the JNK-specific inhibitor SP600125. Moreover, LPS could upregulate the protein level of E3 ubiquitin Ligase Itch, a substrate of JNK kinases. Immunoprecipitation analyses revealed an increase in the association of FTL with Itch, a substrate of JNK kinases, in response to LPS stimulation. SP600125 decreased LPS-induced Itch upregulation. Taken together, these results suggest that LPS stimulation leads to the degradation of FTL through the ubiquitin-proteasome proteolytic pathway, and this FTL degradation is mediated by the JNK/Itch axis in murine macrophage cells.

Keywords

JNK; ferritin light chain; itch.; lipopolysaccharide; ubiquitin.

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