2. Academic Validation
  3. miR-15b-5p promotes HgCl2-induced chicken embryo kidney cells ferroptosis by targeting β-TrCP-mediated ATF4 ubiquitin degradation

miR-15b-5p promotes HgCl2-induced chicken embryo kidney cells ferroptosis by targeting β-TrCP-mediated ATF4 ubiquitin degradation

  • Toxicology. 2024 Feb 6:503:153742. doi: 10.1016/j.tox.2024.153742.
Hong-Yu Fu 1,  Yue Li 1,  Han Cui 1,  Jiu-Zhi Li 1,  Wan-Xue Xu 1,  Xi Wang 1,  Rui-Feng Fan 2
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China.
  • 2 College of Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China. Electronic address: fanruifeng@sdau.edu.cn.
PMID: 38325558 DOI: 10.1016/j.tox.2024.153742
Abstract

Mercuric chloride (HgCl2), a widespread environmental pollutant, induces Ferroptosis in chicken embryonic kidney (CEK) cells. Whereas activating transcription factor 4 (ATF4), a critical mediator of oxidative homeostasis, plays a dual role in Ferroptosis, but its precise mechanisms in HgCl2-induced Ferroptosis remain elusive. This study aims to investigate the function and molecular mechanism of ATF4 in HgCl2-induced Ferroptosis. Our results revealed that ATF4 was downregulated during HgCl2-induced Ferroptosis in CEK cells. Surprisingly, HgCl2 exposure has no significant impact on ATF4 mRNA level. Further investigation indicated that HgCl2 enhanced the expression of the E3 Ligase beta-transducin repeat-containing protein (β-TrCP) and increased ATF4 ubiquitination. Subsequent findings identified that miR-15b-5p as an upstream modulator of β-TrCP, with miR-15b-5p downregulation observed in HgCl2-exposed CEK cells. Importantly, miR-15b-5p mimics suppressed β-TrCP expression and reversed HgCl2-induced cellular Ferroptosis. Mechanistically, HgCl2 inhibited miR-15b-5p, and promoted β-TrCP-mediated ubiquitin degradation of ATF4, thereby inhibited the expression of antioxidant-related target genes and promoted Ferroptosis. In conclusion, our study highlighted the crucial role of the miR-15b-5p/β-TrCP/ATF4 axis in HgCl2-induced nephrotoxicity, offering a new therapeutic target for understanding the mechanism of HgCl2 nephrotoxicity.

Keywords

ATF4; E3 ubiqutin ligase; Ferroptosis; Mercuric chloride; miR-15b-5p.

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