PMID:9535085

Citation	Palmer, LE, Hobbie, S, Galán, JE and Bliska, JB (1998) YopJ of Yersinia pseudotuberculosis is required for the inhibition of macrophage TNF-alpha production and downregulation of the MAP kinases p38 and JNK. Mol. Microbiol. 27:953-65
Abstract	Exposure of macrophages to lipopolysaccharide (LPS) leads to production of the pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-alpha). Previous studies have suggested that pathogenic Yersinia spp. inhibit LPS-mediated production of TNF-alpha in macrophages, and that one of the Yop proteins secreted by the plasmid-encoded type III pathway is required for this activity. We found that TNF-alpha production was inhibited when J774A.1 murine macrophages were infected with wild-type Y. pseudotuberculosis but not with an isogenic ysc mutant defective for Yop secretion. We inactivated multiple yop genes to identify which of these factors are required for the inhibition of TNF-alpha production. A mutant unable to express yopJ was defective for the inhibition of TNF-alpha production. Production of TNF-alpha is regulated at the transcriptional and translational levels by several mitogen-activated protein (MAP) kinases. The MAP kinases p38 and JNK underwent sustained activation in macrophages infected with the yopJ mutant. Conversely, p38 and JNK were downregulated in macrophages infected with the wild-type strain. The ability of the yopJ mutant to downregulate p38 and JNK and to inhibit production of TNF-alpha was restored by the expression of yopJ+ in trans. Therefore, YopJ is required for Y. pseudotuberculosis to downregulate MAP kinases and inhibit the production of TNF-alpha in macrophages.
Links	PubMed
Keywords	Animals; Bacterial Outer Membrane Proteins/genetics; Bacterial Outer Membrane Proteins/physiology; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Cell Line; Cloning, Molecular; Down-Regulation; Enzyme Activation; Gene Expression Regulation, Bacterial; Genetic Complementation Test; Immunoblotting; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides/pharmacology; Macrophages/metabolism; Macrophages/microbiology; Mice; Mitogen-Activated Protein Kinases; Mutation; Tumor Necrosis Factor-alpha/biosynthesis; Tumor Necrosis Factor-alpha/genetics; Yersinia pseudotuberculosis/genetics; Yersinia pseudotuberculosis/pathogenicity; Yersinia pseudotuberculosis/physiology; p38 Mitogen-Activated Protein Kinases
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
YERPS:YOPB		GO:0042536: negative regulation of tumor necrosis factor biosynthetic process	ECO:0000335:		P	occurs_in:CL:0000235	CL:0000235 occurs in human macrophages. Figure 1B shows J774A.1 macrophages were infected with Yersinia pseudotuberculosis strains both able and unable to secrete full-length translocon YopB for 1 hour. Levels of TNF-alpha in media were quantified, with YopB mutants consistently producing twofold more TNF-alpha. Yersinia pseudotuberculosis A0A0N9NJG3 should be the protein ID. This is described as an Uncharacterized protein, I chose this protein designation because there is no YopB for Yersinia pseudotuberculosis.	complete CACAO 13638
YERPS:YOPJ		GO:0042536: negative regulation of tumor necrosis factor biosynthetic process	ECO:0000335: substance quantification evidence		P	occurs_in:CL:0000235	Figure 3b shows that strain YP25, defective for secretion of effector YopJ, had increased macrophage TNF-alpha production after J774A.1 macrophages were infected with Yersinia pseudotuberculosis strains both able and unable to secrete YopJ. Yersinia pseudotuberculosis accuring in human macrophages.	complete CACAO 13639
YERPU:A0A0N9NCU6		GO:1903753: negative regulation of p38MAPK cascade	ECO:0000279:		P	occurs_in:CL:0000235	CL:0000235 occurs in human macrophages. Figure 6 shows J774A.1 macrophages infected with Yersinia pseudotuberculosis strains both able and unable to secrete full-length translocon YopJ for 1 hour, and protein samples were taken to be analyzed by immunoblotting with anti-P38, indicating down-regulation of P38 by YopJ. Yersinia pseudotuberculosis	complete
YERPU:A0A0N9NCU6		GO:0046329: negative regulation of JNK cascade	ECO:0000279:		P	occurs_in:CL:0000235	CL:0000235 occurs in human macrophages. Figure 6c shows J774A.1 macrophages were infected with Yersinia pseudotuberculosis strains both able and unable to secrete full-length translocon YopJ for 1 hour. Cell lysates were taken for immunoblotting with a phosphospecific anti-JNK antibody. Blotting showed YopJ down regulated JNK in macrophages. Yersinia pseudotuberculosis	complete

References

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