2. Academic Validation
  3. A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination

A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination

  • Nat Commun. 2023 Mar 17;14(1):1430. doi: 10.1038/s41467-023-37148-x.
Lihua Qiang # 1 2,  Yong Zhang # 1,  Zehui Lei # 1 2,  Zhe Lu 1 2,  Shasha Tan 1,  Pupu Ge 1,  Qiyao Chai 1,  Mengyuan Zhao 1 2,  Xinwen Zhang 1 2,  Bingxi Li 1,  Yu Pang 3,  Lingqiang Zhang 4,  Cui Hua Liu 5 6,  Jing Wang 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2 Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China.
  • 3 Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China.
  • 4 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China. [email protected].
  • 5 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 6 Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China. [email protected].
  • 7 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • # Contributed equally.
PMID: 36932056 DOI: 10.1038/s41467-023-37148-x
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.

Figures
Products