2. Academic Validation
  3. WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism

WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism

  • Free Radic Biol Med. 2023 Mar 18;S0891-5849(23)00118-1. doi: 10.1016/j.freeradbiomed.2023.03.012.
Qiuhong Xiong 1,  Huimin Sun 2,  Wenxiu Xing 2,  Xin Li 2,  Guangxin Chen 2,  Zhonghua Zhao 2,  Changxin Wu 3,  Ping Li 4
Affiliations

Affiliations

  • 1 Institutes of Biomedical Sciences, Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China. Electronic address: qxiong@sxu.edu.cn.
  • 2 Institutes of Biomedical Sciences, Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China.
  • 3 Institutes of Biomedical Sciences, Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China. Electronic address: cxw20@sxu.edu.cn.
  • 4 Institutes of Biomedical Sciences, Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China. Electronic address: pingli@sxu.edu.cn.
PMID: 36940732 DOI: 10.1016/j.freeradbiomed.2023.03.012
Abstract

Ferritin is the main iron storage protein that plays a pivotal role in the regulation of iron homeostasis. Mutations in the Autophagy protein WD repeat domain 45 (WDR45) that lead to iron overload is associated with the human β-propeller protein-associated neurodegeneration (BPAN). Previous studies have demonstrated that ferritin was decreased in WDR45 deficient cells, but the mechanism remains unclear. In this study, we have demonstrated that the ferritin heavy chain (FTH) could be degraded via chaperone-mediated Autophagy (CMA) in ER stress/p38-dependent pathway. In HeLa cells, inducing the ER stress activated CMA, therefore facilitated the degradation of FTH, and increased the content of Fe2+. However, the increased CMA activity and Fe2+ as well as the decreased FTH by ER stress inducer were restored by pre-treatment with p38 inhibitor. Overexpression of a mutant WDR45 activated CMA thus promoted the degradation of FTH. Furthermore, inhibition of ER stress/p38 pathway resulted in reduced activity of CMA, which consequently elevated the protein level of FTH but reduced the Fe2+ level. Our results revealed that WDR45 mutation dysregulates iron homeostasis by activating CMA, and promotes FTH degradation through ER stress/p38 signaling pathway.

Keywords

BPAN; Chaperone-mediated autophagy; ER stress; FTH; Iron homeostasis; WDR45; p38.

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