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Updated: Jan 11, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
A Pseudomonas aeruginosa quorum-sensing metabolite manipulates macrophage ferroptosis through a methylation pathway
Tianyuan Jia1,2,3, Fengming Li4, Tianzhen Li4
1National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China. jiatianyuan2021@163.com.
Abstract:
Ferroptosis is a type of iron- and lipid peroxidation-dependent programmed cell death that is involved in various diseases. Some pathogens manipulate host ferroptosis for pathogenesis; however, the potential mechanisms of action remain unclear. Pseudomonas aeruginosa is an opportunistic pathogen that relies on iron for its virulence, biofilm formation, and survival. Here, we report that P. aeruginosa employs the quorum-sensing metabolite, Pseudomonas quinolone signal (PQS), to induce ferroptosis in macrophages through a carnosine-N-methyltransferase (CNMT)-transferrin receptor 1 (TFR1) methylation pathway. Specifically, PQS promotes iron-dependent lipid peroxidation to induce ferroptosis in macrophages. Using high-resolution mass spectrometry-based cellular thermal shift assay (MS-CETSA)/thermal proteome profiling, we identify CNMT as the direct intracellular receptor of PQS in macrophages. Mechanistically, PQS binding increases the histidine methyltransferase (His MTase) activity of CNMT, catalysing methylation of TFR1 at His35. This methylation increases TFR1 protein production, resulting in amplified iron acquisition for ferroptosis. Crucially, the PQS-CNMT-TFR1 axis is distinct from canonical bacterial pathogens that exploit host cell death pathways, revealing the unique strategy of P. aeruginosa to exploit host epigenetic machinery.
Insights
Pseudomonas aeruginosa uses Pseudomonas quinolone signal (PQS) to trigger ferroptosis in macrophages. This involves a novel pathway where PQS enhances iron uptake, promoting cell death and pathogen survival.
Area of Science:
- Cell Biology
- Microbiology
- Immunology
Background:
- Ferroptosis, a cell death form driven by iron and lipid peroxidation, is implicated in diseases.
- Pathogens can manipulate host ferroptosis, but mechanisms are often unknown.
- Pseudomonas aeruginosa, an opportunistic pathogen, requires iron for virulence and survival.
Purpose of the Study:
- To elucidate the mechanism by which Pseudomonas aeruginosa induces ferroptosis in host macrophages.
- To identify the specific molecules and pathways involved in P. aeruginosa-mediated ferroptosis.
Main Methods:
- High-resolution mass spectrometry-based cellular thermal shift assay (MS-CETSA) and thermal proteome profiling were employed.
- Investigated the role of Pseudomonas quinolone signal (PQS), carnosine-N-methyltransferase (CNMT), and transferrin receptor 1 (TFR1).
Main Results:
- P. aeruginosa utilizes PQS to induce ferroptosis in macrophages via a CNMT-TFR1 methylation pathway.
- PQS binding to CNMT enhances its methyltransferase activity, leading to TFR1 methylation at His35.
- This methylation increases TFR1 expression, boosting iron acquisition and promoting ferroptosis.
Conclusions:
- P. aeruginosa employs a unique PQS-CNMT-TFR1 axis to induce host macrophage ferroptosis.
- This mechanism involves hijacking host epigenetic machinery for pathogen advantage.
- The findings reveal a novel bacterial strategy distinct from other pathogens exploiting host cell death.
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