A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination

Ferroptosis is a lipid peroxidation-driven and iron-dependent programmed cell death involved in multiple physical processes and various diseases. Emerging evidence suggests that several pathogens manipulate ferroptosis for their pathogenicity and dissemination, but the underlying molecular mechanisms remain elusive. Here, we identify that protein tyrosine phosphatase A (PtpA), an effector secreted by tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis (Mtb), triggers ferroptosis to promote Mtb pathogenicity and dissemination. Mechanistically, PtpA, through its Cys11 site, interacts with host RanGDP to enter host cell nucleus. Then, the nuclear PtpA enhances asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) via targeting protein arginine methyltransferase 6 (PRMT6), thus inhibiting glutathione peroxidase 4 (GPX4) expression, eventually inducing ferroptosis to promote Mtb pathogenicity and dissemination. Taken together, our findings provide insights into molecular mechanisms of pathogen-induced ferroptosis, indicating a potential TB treatment via blocking Mtb PtpA-host PRMT6 interface to target GPX4-dependent ferroptosis.

Automated summary

This research discovers that tuberculosis-causing pathogen Mycobacterium tuberculosis (Mtb) activates iron-dependent cell death, called ferroptosis, through a secreted protein called PtpA, promoting Mtb's pathogenicity and dissemination. The mechanism involves PtpA entering the host cell nucleus and enhancing the methylation of histone H3, inhibiting the expression of glutathione peroxidase 4 (GPX4), ultimately inducing ferroptosis. This study provides insights into the molecular mechanisms of pathogen-induced ferroptosis and suggests a potential tuberculosis treatment by targeting Mtb PtpA-host PRMT6 interface to block GPX4-dependent ferroptosis.