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YTHDF2-mediated m6A modification regulates mRNA stability of Immediate early response gene 3 to modulate cell death

Yue Xing1, Siyuan Mi1, Siqian Chen1

  • 1State Key Laboratory of Animal Biotech Breeding, National Engineering Laboratory for Animal Breeding, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, China.

Frontiers in Cellular and Infection Microbiology
|June 16, 2025
PubMed
Abstract

Insights

Staphylococcus aureus infection in cows reduces YTHDF2, destabilizing IER3 mRNA and causing cell death. Restoring YTHDF2 protects against bovine mastitis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Bovine mastitis caused by Staphylococcus aureus poses a significant economic threat to dairy production.
  • The precise molecular mechanisms governing host cell apoptosis and inflammation during S. aureus infection are not fully understood.
  • This study focuses on the role of N6-methyladenosine (m6A) modification and its reader protein YTHDF2 in bovine mammary epithelial cells.

Purpose of the Study:

  • To investigate the function of YTHDF2 in regulating mRNA stability, apoptosis, and inflammation in Mac-T cells during S. aureus infection.
  • To elucidate the m6A modification pathway's involvement in bovine mastitis.
  • To identify potential genetic markers for breeding mastitis-resistant dairy cattle.

Main Methods:

  • MeRIP-seq, RIP-seq, and RT-qPCR were employed to analyze m6A-modified IER3 mRNA and its interaction with YTHDF2.
  • Apoptosis, necrosis, and mitochondrial function were assessed using YO-PRO-1/PI staining and JC-1 assays.
  • Mac-T cells were utilized to model S. aureus infection in vitro.

Main Results:

  • S. aureus infection led to decreased YTHDF2 expression, destabilizing m6A-modified IER3 mRNA.
  • This destabilization resulted in elevated reactive oxygen species (ROS) levels, impaired mitochondrial function, and increased apoptosis.
  • Overexpression of YTHDF2 reversed these effects, restoring mRNA stability and preserving mitochondrial function.

Conclusions:

  • YTHDF2 plays a crucial role in regulating m6A-modified mRNA stability, thereby modulating apoptosis and inflammation in response to S. aureus infection.
  • These findings offer novel insights into the molecular pathogenesis of bovine mastitis.
  • The study identifies potential genetic markers for developing mastitis-resistant dairy breeds.
Keywords:
Staphylococcus aureusYTHDF2apoptosis and necrosisbovine mastitism6A modification

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