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Pseudomonas aeruginosa manipulates a CNMT-TFR1 methylation pathway to drive macrophage ferroptosis via quorum sensing molecule PQS

ABSTRACT: Pseudomonas aeruginosa employs quorum sensing (QS) small molecules such as Pseudomonas Quinolone Signal (PQS) to manipulate host cell death. Although PQS triggers several cell death modalities, its role in ferroptosis remains enigmatic. Here, we reported that PQS induces ferroptosis in macrophages through a previously unrecognized carnosine-N-methyltransferase (CNMT)-transferrin receptor 1 (TFR1) methylation pathway. Using thermal proteome profilingscreening, we identified CNMT as the direct intracellular receptor of PQS in macrophage. Mechanistically, PQS binding activates CNMT’s histidine methyltransferase activity, catalyzing H35 methylation on TFR1. This methylation modification increases TFR1 expressions, amplifying iron acquisition and lipid peroxidation for ferroptosis. Crucially, the PQS-CNMT-TFR1 axis is distinct from canonical bacterial pathogens that exploit host cell death pathways, revealing P. aeruginosa’s unique strategy to exploit host epigenetic machinery. Our findings redefine QS molecules as mediators of interkingdom signaling and position CNMT-TFR1 methylation as therapeutic targets aimed at blocking ferroptosis-driven immunopathology to mitigate P. aeruginosa virulence.

ORGANISM(S): Mus Musculus

SUBMITTER: Chris Soon Heng Tan

PROVIDER: PXD061292 | iProX | Thu Feb 27 00:00:00 GMT 2025

REPOSITORIES: iProX

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Pseudomonas aeruginosa manipulates a CNMT-TFR1 methylation pathway to drive macrophage ferroptosis via quorum sensing molecule PQS

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