<i>Salmonella</i> Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy

Despite decades of research on effective methods to resist <i>Salmonella enterica</i> serovar Typhimurium (<i>S</i>. Typhimurium) pathogenicity, the mechanisms of <i>S</i>. Typhimurium-host interactions have not been fully determined. <i>S</i>. 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 <i>S</i>. Typhimurium replication and survival in the host. <i>S</i>. Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated <i>S</i>. Typhimurium proliferation in cells. <i>S</i>. 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 <i>S</i>. Typhimurium. In conclusion, <i>S</i>. Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.<b>Abbreviation</b>: 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: <i>Salmonell</i>a-containing vacuoles; siRNA: small interfering RNA; SPI-2: <i>Salmonella</i> pathogenicity island 2; SseJ: secretion system effector J; <i>S</i>. Typhimurium: <i>Salmonella enterica</i> serovar Typhimurium; <i>S</i>.T-<i>ΔSseJ</i>: SseJ gene-deleted <i>Salmonella</i> Typhimurium strains; <i>S</i>.T-<i>CΔSseJ</i>: SseJ-complemented <i>Salmonella</i> Typhimurium strains; WT: wild-type.