Disease relevance of yopH

• Yersinia pestis, the bacterium which causes the bubonic plague, also contains a gene closely related to yopH [1].
• The vaccinia virus VH1 gene, like yopH in the Yersinia bacteria, encodes a protein phosphatase [1].
• In order to facilitate studies of in vivo expression of yopE and yopH we constructed operon fusions between these two genes and a promoterless luxAB operon from Vibrio harveyi in Y. pseudotuberculosis [2].
• Several of the new Ysps are homologous to other virulence factors, including YspP with similarity to the Yersinia protein tyrosine phosphatase YopH and YspK with similarity to the Shigella serine/threonine kinase OspG [3].
• Furthermore, we found that either YopE or YopH prevented Listeria invasion, whereas only YopE prevented Edwardsiella and Shigella invasion [4].

High impact information on yopH

• Yersinia have the ability to directly suppress T lymphocyte activation through the virulence factor YopH, a tyrosine phosphatase [5].
• This efficient inhibition is traced to specific targeting by YopH of the adaptor proteins, linker for activation of T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kD (SLP-76), which are crucial for T cell antigen receptor (TCR) signaling [5].
• The 120- and 55-kD proteins that coprecipitate with YopHC403A exhibited the in vitro activity of protein tyrosine kinases (PTKases), suggesting that YopH dephosphorylates activated tyrosine kinases in vivo [6].
• We infected the murine macrophage-like cell line J774A.1 with Yersinia pseudotuberculosis and investigated the specificity of YopH and YopHC403A, a catalytically inactive mutant derivative, for eukaryotic phosphoproteins [6].
• RESULTS: H. pylori induced phosphorylation of 125-130-kilodalton proteins, similar in size to the target proteins of Yersinia YopH [7].

Chemical compound and disease context of yopH

• Aurintricarboxylic acid blocks in vitro and in vivo activity of YopH, an essential virulent factor of Yersinia pestis, the agent of plague [8].
• YopH of Yersinia pseudotuberculosis interrupts early phosphotyrosine signalling associated with phagocytosis [9].

Biological context of yopH

• We subsequently analyzed the contribution of yopH, -O, -P, -E, -M, -T, and -Q deletions to pathogenicity after oral and intravenous infection of mice [10].
• Insertional inactivation of the yopH gene abrogated the inhibition of phagocytosis of antibody- and complement-opsonized Y. enterocolitica by human granulocytes but not of the f-MLP-induced O2- production by granulocytes or tyrosine phosphorylation of granulocyte proteins [11].
• The yscM gene shares homology with yopH, the adjacent gene on the pYV plasmid [12].
• In a first construction, an operon fusion was obtained between ctxB and yopH so that CT-B and a truncated YopH protein were produced [13].
• The action of YopH on host proteins appears to break down signal transduction mechanisms in many cell types including those of the immune system [1].

Anatomical context of yopH

• A yopH mutant strain specifically fails to colonize the mesenteric lymph nodes, but yopE and yopO mutant strains showed only minor defects in persistence in intestinal and lymph tissues [14].
• After oral inoculation of mice, Yersinia pseudotuberculosis yopE and yopH mutants colonize the intestines and Peyer's patches in single-strain infections but fail to persist in competition with wild-type Y. pseudotuberculosis, indicating that these two infection models provide different insights into the roles of Yops [15].
• We suggest that p130Cas and FAK are substrates for YopH and that the dephosphorylation of these proteins impairs the uptake of Yersinia pseudotuberculosis into HeLa cells [16].
• A catalytically inactive 'substrate-trapping' mutant, YopHC403S, was used as a probe to determine where YopH substrates localize in eukaryotic cells [17].
• Identification of p130Cas as a substrate of Yersinia YopH (Yop51), a bacterial protein tyrosine phosphatase that translocates into mammalian cells and targets focal adhesions [17].

Associations of yopH with chemical compounds

• The transcription of the yopH gene for YopH phosphatase in these maltose mutants was unchanged and revealed a maltose mutation impaired in the secretion of Yop proteins instead of their expression [18].
• Ingestion of a yopH mutant was dependent on tyrosine kinase activity [9].
• Conversely, YopH destabilized focal adhesions, even in the absence of YopE, as shown by loss of phosphotyrosine staining [17].
• In particular, we note that residues Arg-404, Glu-290, Asp-356, and a bound water (WAT185) participate in a unique H-bonding network with the hydroxyl group ortho to the sulfuryl moiety, which may be exploited to design more potent and specific YopH inhibitors [19].
• The most potent and specific YopH inhibitor is aurintricarboxylic acid (ATA), which exhibits a Ki value of 5 nm for YopH and displays 6-120-fold selectivity in favor of YopH against a panel of mammalian PTPs [8].

Other interactions of yopH

• The promoter region of the yopE and yopH genes were compared and four conserved motifs identified [20].
• Finally, competition infections with Y. pseudotuberculosis mutants with various abilities to induce inflammation demonstrated that survival of the yopE, but not the yopH, mutant was consistently decreased in inflamed tissues [15].
• In competition infections with wild-type Y. pseudotuberculosis, the presence of wild-type bacteria severely hindered the ability of the yopH, yopE, and yopO mutants to persist in many tissues, suggesting that the wild-type bacteria either fills colonization niches or elicits host responses that the yop mutants are unable to withstand [14].
• Derivatives of the virulence plasmid pIB1 harboring mutations in yadA, yopE, or yopH or in a low-calcium-response regulatory locus were introduced into a Yersinia pseudotuberculosis YPIII strain defective for Inv [21].

Analytical, diagnostic and therapeutic context of yopH

• The primary signal transducer for the T cell antigen receptor, the Lck tyrosine kinase, was specifically precipitated by a substrate-trapping YopH mutant, and Lck was dephosphorylated at its positive regulatory site, Tyr-394, in cells containing active YopH [22].
• J774A.1 cells were infected with Y. pestis KIM5 in the presence of a protective polyclonal anti-LcrV antibody or a nonprotective polyclonal anti-YopM antibody, and delivery of YopH and YopE into the cytoplasm was assayed by immunoblotting [23].
• We show here that immunoprecipitation of YopH from lysates of J774 cells infected with Y. pseudotuberculosis expressing an inactive form of YopH resulted in co-precipitation of certain phosphotyrosine proteins [24].
• Using ELISA, a significant response by IgG-class antibodies to YopH protein was evident in the sera from rabbits both orogastrically and intravenously infected with the virulent (pYV+) Y. enterocolitica O:9 W836 strain [25].

References