Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection.
Animals
Bacterial Outer Membrane Proteins
/ immunology
Intracellular Signaling Peptides and Proteins
/ genetics
MAP Kinase Signaling System
/ genetics
Mice
Mice, Inbred BALB C
Mice, Knockout
Neutrophils
/ immunology
Protein Tyrosine Phosphatases
/ immunology
Reactive Oxygen Species
/ immunology
Signal Transduction
/ genetics
Yersinia pseudotuberculosis
/ immunology
Yersinia pseudotuberculosis Infections
/ genetics
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
09
01
2020
accepted:
23
04
2020
revised:
21
05
2020
pubmed:
12
5
2020
medline:
22
7
2020
entrez:
12
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32392230
doi: 10.1371/journal.ppat.1008576
pii: PPATHOGENS-D-20-00039
pmc: PMC7241846
doi:
Substances chimiques
Bacterial Outer Membrane Proteins
0
Intracellular Signaling Peptides and Proteins
0
Reactive Oxygen Species
0
src kinase associated phosphoprotein 2
0
Protein Tyrosine Phosphatases
EC 3.1.3.48
yopH protein, Yersinia
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008576Subventions
Organisme : NIAID NIH HHS
ID : R01 AI107055
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI113166
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007422
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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