Sun Dage, Gou Hongchao, Zhang Yu, Li Jiayi, Dai Changzhi, Shen Haiyan, Chen Kaifeng, Wang Yu, Pan Peng, Zhu Ting, Xu Chenggang, Shan Tongling, Liao Ming, Zhang Jianmin
National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Key Laboratory of Zoonoses, Ministry of Agriculture, Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Guangzhou, China.
Autophagy. 2025 Jun;21(6):1228-1244. doi: 10.1080/15548627.2025.2462511. Epub 2025 Feb 14.
Despite decades of research on effective methods to resist serovar Typhimurium (. Typhimurium) pathogenicity, the mechanisms of . Typhimurium-host interactions have not been fully determined. . 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 . Typhimurium replication and survival in the host. . Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated . Typhimurium proliferation in cells. . 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 . Typhimurium. In conclusion, . Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.: ACTB: actin beta; BafA1: bafilomycin A; 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: a-containing vacuoles; siRNA: small interfering RNA; SPI-2: pathogenicity island 2; SseJ: secretion system effector J; . Typhimurium: serovar Typhimurium; .T-: SseJ gene-deleted Typhimurium strains; .T-: SseJ-complemented Typhimurium strains; WT: wild-type.
尽管数十年来一直在研究抵抗鼠伤寒血清型沙门氏菌（鼠伤寒沙门氏菌）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明确。由于其地方性、高发病率以及控制和预防措施应用困难，鼠伤寒沙门氏菌被认为是全球公共卫生领域一种重要的人畜共患病。在此，我们介绍一种新型细菌因子，分泌系统效应蛋白J（SseJ）及其相互作用的宿主蛋白， prohibitin 2（PHB2）。我们探究了SseJ是否影响鼠伤寒沙门氏菌在宿主体内的复制和存活。鼠伤寒沙门氏菌感染会导致严重的线粒体损伤和线粒体自噬，这促进了鼠伤寒沙门氏菌在细胞内的增殖。鼠伤寒沙门氏菌的SseJ在自噬受体PHB2的辅助下，激活了PTEN诱导激酶1（PINK1）-帕金RBR E3泛素蛋白连接酶（PRKN）-自噬体依赖性线粒体自噬途径，以实现细菌的存活和持续感染。此外，抑制线粒体自噬可减轻鼠伤寒沙门氏菌的致病性。总之，靶向SseJ-PHB2介导的宿主线粒体自噬途径可对抗鼠伤寒沙门氏菌感染。：ACTB：肌动蛋白β；BafA1：巴弗洛霉素A；CCCP：羰基氰化物间氯苯腙；co-IP：免疫共沉淀；CFU：集落形成单位；COX4/COXIV：细胞色素c氧化酶亚基4；CQ：氯喹；hpi：细菌感染后小时数；MAP1LC3B/LC3B：微管相关蛋白1轻链3β；Mdivi-1：线粒体自噬抑制剂线粒体分裂抑制剂1；MFN2：线粒体融合蛋白2；MG132：Z-亮氨酰-亮氨酰-亮氨酸；MOI：感染复数；mtDNA：线粒体DNA；PBS：磷酸盐缓冲盐水；PGAM5：PGAM家族成员5，线粒体丝氨酸/苏氨酸蛋白磷酸酶；PHB2：prohibitin 2；PINK1：PTEN诱导激酶1；qPCR：定量实时逆转录PCR；Roc-A：罗卡酰胺A；PRKN/帕金：帕金RBR E3泛素蛋白连接酶；SCVs：含沙门氏菌的液泡；siRNA：小干扰RNA；SPI-2：毒力岛2；SseJ：分泌系统效应蛋白J；鼠伤寒沙门氏菌：鼠伤寒血清型沙门氏菌；SseJ基因缺失的鼠伤寒沙门氏菌菌株；SseJ互补的鼠伤寒沙门氏菌菌株；WT：野生型
