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Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection


Autoři: Lamyaa Shaban aff001;  Giang T. Nguyen aff002;  Benjamin D. Mecsas-Faxon aff003;  Kenneth D. Swanson aff004;  Shumin Tan aff001;  Joan Mecsas aff001
Působiště autorů: Graduate Program in Molecular Microbiology, Tufts Graduate Biomedical Sciences, Boston Massachusetts, United States of America aff001;  Graduate Program in Immunology, Tufts Graduate Biomedical Sciences, Boston Massachusetts, United States of America aff002;  Dept of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston Massachusetts, United States of America aff003;  Brain Tumor Center and Neuro-Oncology Unit, Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston Massachusetts, United States of America aff004
Vyšlo v časopise: Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection. PLoS Pathog 16(5): e32767. doi:10.1371/journal.ppat.1008576
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008576

Souhrn

Yersinia suppress neutrophil responses by using a type 3 secretion system (T3SS) to inject 6–7 Yersinia effector proteins (Yops) effectors into their cytoplasm. YopH is a tyrosine phosphatase that causes dephosphorylation of the adaptor protein SKAP2, among other targets in neutrophils. SKAP2 functions in reactive oxygen species (ROS) production, phagocytosis, and integrin-mediated migration by neutrophils. Here we identify essential neutrophil functions targeted by YopH, and investigate how the interaction between YopH and SKAP2 influence Yersinia pseudotuberculosis (Yptb) survival in tissues. The growth defect of a ΔyopH mutant was restored in mice defective in the NADPH oxidase complex, demonstrating that YopH is critical for protecting Yptb from ROS during infection. The growth of a ΔyopH mutant was partially restored in Skap2-deficient (Skap2KO) mice compared to wild-type (WT) mice, while induction of neutropenia further enhanced the growth of the ΔyopH mutant in both WT and Skap2KO mice. YopH inhibited both ROS production and degranulation triggered via integrin receptor, G-protein coupled receptor (GPCR), and Fcγ receptor (FcγR) stimulation. SKAP2 was required for integrin receptor and GPCR-mediated ROS production, but dispensable for degranulation under all conditions tested. YopH blocked SKAP2-independent FcγR-stimulated phosphorylation of the proximal signaling proteins Syk, SLP-76, and PLCγ2, and the more distal signaling protein ERK1/2, while only ERK1/2 phosphorylation was dependent on SKAP2 following integrin receptor activation. These findings reveal that YopH prevents activation of both SKAP2-dependent and -independent neutrophilic defenses, uncouple integrin- and GPCR-dependent ROS production from FcγR responses based on their SKAP2 dependency, and show that SKAP2 is not required for degranulation.

Klíčová slova:

Fc receptors – G protein coupled receptors – Integrins – Neutrophils – Phagocytosis – Phosphorylation – Redox signaling – Spleen


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