1. PIAS3 acts as a zinc sensor under zinc deficiency and plays an important role in myocardial ischemia/reperfusion injury.
- Author
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Zhao H, Liu D, Sun S, Yu J, Bian X, Cheng X, Yang Q, Yu Y, and Xu Z
- Subjects
- Animals, Mice, Male, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Humans, Mice, Inbred C57BL, Myocardial Infarction metabolism, Myocardial Infarction genetics, Myocardial Infarction pathology, Molecular Chaperones genetics, Molecular Chaperones metabolism, Zinc metabolism, Zinc deficiency, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury genetics, Myocardial Reperfusion Injury pathology, Protein Inhibitors of Activated STAT metabolism, Protein Inhibitors of Activated STAT genetics, Ubiquitination, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics
- Abstract
Alterations in zinc transporter expression in response to zinc loss protect cardiac cells from ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms how cardiac cells sense zinc loss remains unclear. Here, we found that zinc deficiency induced ubiquitination and degradation of the protein inhibitor of activated STAT3 (PIAS3), which can alleviate myocardial I/R injury by activating STAT3 to promote the expression of ZIP family zinc transporter genes. The RING finger domain within PIAS3 is vital for PIAS3 degradation, as PIAS3-dRing (missing the RING domain) and PIAS3-Mut (zinc-binding site mutation) were resistant to degradation in the setting of zinc deficiency. Meanwhile, the RING finger domain within PIAS3 is critical for the inhibition of STAT3 activation. Moreover, PIAS3 knockdown increased cardiac Zn
2+ levels and reduced myocardial infarction in mouse hearts subjected to I/R, whereas wild-type PIAS3 overexpression, but not PIAS3-Mut, reduced cardiac Zn2+ levels, and exacerbated myocardial infarction. These findings elucidate a unique mechanism of zinc sensing, showing that fast degradation of the zinc-binding regulatory protein PIAS3 during zinc deficiency can correct zinc dyshomeostasis and alleviate reperfusion injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
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