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PRMT-7/PRMT7 activates HLH-30/TFEB to guard plasma membrane integrity compromised by bacterial pore-forming toxins

Hui-Chen Hsieh1,2, I-Hsiang Huang1, Shao-Wen Chang1

  • 1Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Autophagy
|January 23, 2024
PubMed

Insights

Protein arginine methyltransferase-7 (PRMT-7) activates HLH-30/TFEB, a cellular defense against bacterial pore-forming toxins (PFTs). This methylation facilitates nuclear entry, protecting host plasma membrane integrity in both worms and humans.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pathogen-Host Interactions

Background:

  • Bacterial pore-forming toxins (PFTs) are key virulence factors that compromise host plasma membrane integrity (PMI).
  • The intrinsic cellular defense (INCED) pathway, mediated by HLH-30/TFEB, protects the intestinal epithelium from PFTs in *C. elegans*. However, the precise mechanism of HLH-30/TFEB activation by PFTs remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which PFTs fully activate HLH-30/TFEB.
  • To identify host factors involved in the intrinsic cellular defense against PFT-induced membrane damage.
  • To investigate the evolutionary conservation of this defense mechanism.

Main Methods:

  • Utilized *C. elegans* models to study PFT-host interactions and HLH-30 activation.
  • Employed biochemical assays to assess protein methylation and nuclear localization.
  • Validated findings in human intestinal cell lines to confirm evolutionary conservation.

Main Results:

  • Identified PRMT-7 (protein arginine methyltransferase-7) as essential for PFT-induced HLH-30 nuclear translocation and activation.
  • Demonstrated that PRMT-7 methylates HLH-30 on its RAG complex binding domain, promoting its nuclear entry.
  • Showed that human PRMT7 orthologs are conserved in regulating TFEB localization and repairing PFT-induced plasma membrane damage.

Conclusions:

  • Unveiled a novel post-translational regulation of HLH-30/TFEB by PRMT-7/PRMT7 through methylation.
  • Established PRMT-7/PRMT7 as a critical component of the evolutionarily conserved INCED pathway against PFTs in metazoans.
  • Provided insights into host strategies for maintaining plasma membrane integrity against bacterial toxins.
Keywords:
Intrinsic cellular defense (INCED)plasma membrane integrity (PMI)pore-forming toxin (PFT)protein arginine methyltransferase-7 (PRMT7/PRMT-7)transcription factor EB (TFEB/HLH-30)

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