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.

Ferroptosis 是一种脂质过氧化驱动和铁依赖性程序性细胞死亡，涉及多种物理过程和各种疾病。新出现的证据表明，几种病原体操纵铁死亡的致病性和传播，但潜在的分子机制仍然难以捉摸。在这里，我们确定蛋白酪氨酸磷酸酶 A (PtpA)，一种由结核病 (TB) 引起的病原体结核分枝杆菌分泌的效应物(Mtb)，触发铁死亡以促进 Mtb 致病性和传播。从机制上讲，PtpA 通过其 Cys11 位点与宿主 RanGDP 相互作用以进入宿主细胞核。然后，核 PtpA 通过靶向蛋白精氨酸甲基转移酶 6 (PRMT6) 增强组蛋白 H3 精氨酸 2 (H3R2me2a) 的不对称二甲基化，从而抑制谷胱甘肽过氧化物酶 4 (GPX4) 表达，最终诱导铁死亡促进 Mtb 致病性和传播。综上所述，我们的研究结果提供了对病原体诱导的铁死亡的分子机制的见解，表明通过阻断 Mtb PtpA-宿主 PRMT6 界面靶向 GPX4 依赖性铁死亡的潜在结核病治疗。