State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
Front Cell Infect Microbiol. 2022 Feb 4;12:825824. doi: 10.3389/fcimb.2022.825824. eCollection 2022.
Programmed cell death plays an important role in modulating host immune defense and pathogen infection. Ferroptosis is a type of inflammatory cell death induced by intracellular iron-dependent accumulation of toxic lipid peroxides. Although ferroptosis has been associated with cancer and other sterile diseases, very little is known about the role of ferroptosis in modulating host-pathogen interactions. We show that accumulation of the secondary messenger bis-(3',5')-cyclic dimeric GMP (c-di-GMP) in the pathogenic bacterium () triggers a non-canonical ferroptosis pathway in infected HeLa cells. Moreover, we observed that the dysregulation of c-di-GMP in promotes iron accumulation, mitochondrial dysfunction, and production of reactive oxygen species, all of which that can be blocked by iron chelator. Importantly, unlike classical ferroptosis that is executed excess lipid peroxidation, no lipid peroxidation was detected in the infected cells. Furthermore, lipoxygenases inhibitors and lipophilic antioxidants are not able to suppress morphological changes and cell death induced by mutant producing excess c-di-GMP, and this c-di-GMP dysregulation attenuates bacterial virulence . Collectively, our results reveal a novel non-canonical ferroptosis pathway mediated by bacterial c-di-GMP and provide evidence for a role of ferroptosis in the regulation of pathogen infection.
程序性细胞死亡在调节宿主免疫防御和病原体感染方面起着重要作用。铁死亡是一种由细胞内铁依赖性有毒脂质过氧化物积累引起的炎症性细胞死亡。尽管铁死亡与癌症和其他无菌性疾病有关，但人们对铁死亡在调节宿主-病原体相互作用中的作用知之甚少。我们表明，病原体 () 中二信使双-(3',5')-环二鸟苷酸 (c-di-GMP) 的积累在感染的 HeLa 细胞中触发了一种非典型的铁死亡途径。此外，我们观察到 c-di-GMP 在 中的失调促进了铁的积累、线粒体功能障碍和活性氧的产生，所有这些都可以被铁螯合剂阻断。重要的是，与经典的铁死亡不同，铁死亡是由脂质过氧化过度引起的，在感染的细胞中没有检测到脂质过氧化。此外，脂加氧酶抑制剂和亲脂性抗氧化剂不能抑制由产生过量 c-di-GMP 的突变体诱导的形态变化和细胞死亡，这种 c-di-GMP 失调会降低细菌的毒力。总之，我们的研究结果揭示了一种由细菌 c-di-GMP 介导的新型非典型铁死亡途径，并为铁死亡在调节病原体感染中的作用提供了证据。
