A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination.
Lihua QiangYong ZhangZehui LeiZhe LuShasha TanPupu GeQiyao ChaiMengyuan ZhaoXinwen ZhangBingxi LiYu PangLingqiang ZhangCui Hua LiuJing WangPublished in: Nature communications (2023)
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.
Keyphrases
- mycobacterium tuberculosis
- cell death
- pulmonary tuberculosis
- biofilm formation
- binding protein
- regulatory t cells
- candida albicans
- dendritic cells
- amino acid
- physical activity
- single cell
- mental health
- protein protein
- escherichia coli
- oxidative stress
- cell therapy
- staphylococcus aureus
- diabetic rats
- high glucose
- multidrug resistant
- mesenchymal stem cells
- pseudomonas aeruginosa