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A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination

Lihua Qiang, Yong Zhang, Zehui Lei, Zhe Lu, Shasha Tan, Pupu Ge, Qiyao Chai, Mengyuan Zhao, Xinwen Zhang, Bingxi Li, Yu Pang, Lingqiang Zhang (zhanglq@nic.bmi.ac.cn), Cui Hua Liu (liucuihua@im.ac.cn) and Jing Wang (wangj6@im.ac.cn)
Additional contact information
Lihua Qiang: Chinese Academy of Sciences
Yong Zhang: Chinese Academy of Sciences
Zehui Lei: Chinese Academy of Sciences
Zhe Lu: Chinese Academy of Sciences
Shasha Tan: Chinese Academy of Sciences
Pupu Ge: Chinese Academy of Sciences
Qiyao Chai: Chinese Academy of Sciences
Mengyuan Zhao: Chinese Academy of Sciences
Xinwen Zhang: Chinese Academy of Sciences
Bingxi Li: Chinese Academy of Sciences
Yu Pang: Capital Medical University
Lingqiang Zhang: Beijing Institute of Lifeomics
Cui Hua Liu: Chinese Academy of Sciences
Jing Wang: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37148-x

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