Fig. 1. Mtb induces host cell ferroptosis to promote its pathogenicity and dissemination through its effector protein PtpA.
In host cells, the system xc− imports cystine, which is then reduced to cysteine for GSH synthesis. GPX4 utilizes GSH as a co-factor to neutralize lipid peroxides for ferroptosis suppression. Mtb-secreted effector protein PtpA enters the host cell nucleus by interacting with Ran-GTP, and promotes PRMT6-mediated H3R2me2a on the GPX4 promoter. This results in decreased GPX4 expression and ferroptosis induction in host cells, contributing to Mtb pathogenicity and dissemination. GSH glutathione; GPX4 glutathione peroxidase 4; Mtb Mycobacterium tuberculosis; PRMT6 protein arginine methyltransferase 6; PtpA protein tyrosine phosphatase A; Ran-GDP GDP-bound Ran GTPase.