2. Academic Validation
  3. PIAS3 acts as a zinc sensor under zinc deficiency and plays an important role in myocardial ischemia/reperfusion injury

PIAS3 acts as a zinc sensor under zinc deficiency and plays an important role in myocardial ischemia/reperfusion injury

  • Free Radic Biol Med. 2024 May 13:221:188-202. doi: 10.1016/j.freeradbiomed.2024.05.025.
Huanhuan Zhao 1,  Dan Liu 2,  Sha Sun 3,  Jing Yu 2,  Xiyun Bian 4,  Xinxin Cheng 5,  Qing Yang 6,  Yonghao Yu 7,  Zhelong Xu 8
Affiliations

Affiliations

  • 1 Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin, 300070, China. Electronic address: zhaohuan.66@163.com.
  • 2 Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.
  • 3 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 4 Tianjin Key Laboratory of Epigenetics for Organ Development of Preterm Infants, Tianjin Fifth Central Hospital, Tianjin, 300450, China.
  • 5 Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin, 300070, China. Electronic address: chxxtmu@163.com.
  • 6 Department of Cardiology, General Hospital, Tianjin Medical University, Tianjin 300052, China. Electronic address: yangqtjs@163.com.
  • 7 Department of Anesthesiology, General Hospital, Tianjin Medical University, Tianjin 300052, China. Electronic address: yuyhtmu@163.com.
  • 8 Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin, 300070, China; Department of Cardiology, General Hospital, Tianjin Medical University, Tianjin 300052, China; Department of Anesthesiology, General Hospital, Tianjin Medical University, Tianjin 300052, China. Electronic address: zxu@tmu.edu.cn.
PMID: 38750767 DOI: 10.1016/j.freeradbiomed.2024.05.025
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 Zn2+ 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.

Keywords

Zinc deficiency/PIAS3/STAT3/Zinc transporters/RING finger domain/ myocardial ischemia-reperfusion injury.

Figures
Products
Inhibitors & Agonists
Other Products