鼠伤寒沙门氏菌通过其效应物 SseJ 诱导的 PHB2 介导的有丝分裂持续感染宿主。

Autophagy Pub Date : 2025-02-14 DOI:10.1080/15548627.2025.2462511

Dage Sun, Hongchao Gou, Yu Zhang, Jiayi Li, Changzhi Dai, Haiyan Shen, Kaifeng Chen, Yu Wang, Peng Pan, Ting Zhu, Chenggang Xu, Tongling Shan, Ming Liao, Jianmin Zhang

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引用次数: 0

摘要

尽管数十年来人们一直在研究抵抗鼠伤寒沙门氏菌（S. Typhimurium）致病性的有效方法，但鼠伤寒沙门氏菌与宿主相互作用的机制尚未完全确定。鼠伤寒沙门氏菌因其地方流行性、高发病率和难以应用控制和预防措施等特点而成为全球公共卫生领域的重要人畜共患病。在此，我们介绍了一种新型细菌因子--分泌系统效应因子 J（SseJ）及其交互宿主蛋白 PHB2（禁止素 2）。我们探讨了 SseJ 是否会影响伤寒杆菌在宿主体内的复制和存活。鼠伤寒杆菌感染会造成严重的线粒体损伤和有丝分裂，从而促进鼠伤寒杆菌在细胞中的增殖。伤寒杆菌SseJ激活了PINK1（PTEN诱导激酶1）-PRKN（parkin RBR E3泛素蛋白连接酶）-依赖于自噬体的有丝分裂途径，在有丝分裂受体PHB2的帮助下，细菌得以存活并持续感染。此外，抑制有丝分裂可减轻伤寒杆菌的致病性。总之，可以通过靶向 SseJ-PHB2- 介导的宿主线粒体自噬途径来抑制伤寒杆菌感染。

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Salmonella Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy.

Despite decades of research on effective methods to resist Salmonella enterica serovar Typhimurium (S. Typhimurium) pathogenicity, the mechanisms of S. Typhimurium-host interactions have not been fully determined. S. Typhimurium is characterized as an important zoonosis in public health worldwide because of its endemicity, high morbidity, and difficulty in applying control and prevention measures. Herein, we introduce a novel bacterial factor, secretion system effector J (SseJ), and its interactive host protein, PHB2 (prohibitin 2). We explored whether SseJ affected S. Typhimurium replication and survival in the host. S. Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated S. Typhimurium proliferation in cells. S. Typhimurium SseJ activated the PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase)-autophagosome-dependent mitophagy pathway, aided by the mitophagy receptor PHB2, for bacterial survival and persistent infection. Moreover, suppression of mitophagy alleviated the pathogenicity of S. Typhimurium. In conclusion, S. Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.Abbreviation: ACTB: actin beta; BafA1: bafilomycin A₁; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; co-IP: co-immunoprecipitation; CFU: colony-forming units; COX4/COXIV: cytochrome c oxidase subunit 4; CQ: chloroquine; hpi: h post-bacterial infection; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1:mitophagy inhibitor mitochondrial division inhibitor 1; MFN2: mitofusin 2; MG132: z-leu-leu-leucinal; MOI: multiplicity of infection; mtDNA: mitochondrial DNA; PBS: phosphate-buffered saline; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; qPCR: quantitative real-time reverse transcription PCR; Roc-A: Rocaglamide A; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; SCVs: Salmonella-containing vacuoles; siRNA: small interfering RNA; SPI-2: Salmonella pathogenicity island 2; SseJ: secretion system effector J; S. Typhimurium: Salmonella enterica serovar Typhimurium; S.T-ΔSseJ: SseJ gene-deleted Salmonella Typhimurium strains; S.T-CΔSseJ: SseJ-complemented Salmonella Typhimurium strains; WT: wild-type.

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Autophagy

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