miR-15b-5p promotes HgCl2-induced chicken embryo kidney cells ferroptosis by targeting β-TrCP-mediated ATF4 ubiquitin degradation
TOXICOLOGY(2024)
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 (beta-TrCP) and increased ATF4 ubiquitination. Subsequent findings identified that miR-15b-5p as an upstream modulator of beta-TrCP, with miR-15b-5p downregulation observed in HgCl2-exposed CEK cells. Importantly, miR-15b-5p mimics suppressed beta-TrCP expression and reversed HgCl2-induced cellular ferroptosis. Mechanistically, HgCl2 inhibited miR-15b-5p, and promoted beta-TrCP-mediated ubiquitin degradation of ATF4, thereby inhibited the expression of antioxidantrelated target genes and promoted ferroptosis. In conclusion, our study highlighted the crucial role of the miR-15b-5p/beta-TrCP/ATF4 axis in HgCl2-induced nephrotoxicity, offering a new therapeutic target for understanding the mechanism of HgCl2 nephrotoxicity.
MoreTranslated text
Key words
Mercuric chloride,Ferroptosis,ATF4,E3 ubiqutin ligase,miR-15b-5p
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined