Aurintricarboxylic Acid Blocks in Vitro and in Vivo Activity of YopH, an Essential Virulent Factor of Yersinia pestis, the Agent of Plague

Fubo Liang, Zhonghui Huang, Seung Yub Lee, Jiao Liang, Maya I. Ivanov, Andres Alonso, James B. Bliska, David S. Lawrence, Tomas Mustelin, Zhong-Yin Zhang

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to Bubonic Plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. YopH is an essential virulence factor whose protein-tyrosine phosphatase (PTP) activity is required for Yersinia pathogenicity. Consequently, there is considerable interest in developing potent and selective YopH inhibitors as novel anti-plague agents. We have screened a library of 720 structurally diverse commercially available carboxylic acids and identified 26 YopH inhibitors with IC50 values below 100 μM. 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. To determine whether ATA can block the activity of YopH in a cellular context, we have examined the effect of ATA on T-cell signaling in human Jurkat cells transfected with YopH. We show that YopH severely decreases the T-cell receptor-induced cellular tyrosine phosphorylation, ERK1/2 activity, and interleukin-2 transcriptional activity. We demonstrate that ATA can effectively block the inhibitory activity of YopH and restore normal T-cell function. These results provide a proof-of-concept for the hypothesis that small molecule inhibitors that selectively target YopH may be therapeutically useful. In addition, it is expected that potent and selective YopH inhibitors, such as ATA, should be useful reagents to delineate YopH's cellular targets in plague and other pathogenic conditions caused by Yersinia infection.

Original languageEnglish (US)
Pages (from-to)41734-41741
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number43
DOIs
StatePublished - Oct 24 2003
Externally publishedYes

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Aurintricarboxylic Acid
Yersinia pestis
Plague
Yersinia
T-cells
Yersinia Infections
Cell signaling
T-Lymphocytes
Phosphorylation
Protein Tyrosine Phosphatases
Weapons
Jurkat Cells
Gastrointestinal Diseases
Military operations
Virulence Factors
T-Cell Antigen Receptor
Carboxylic Acids
Inhibitory Concentration 50
Libraries
Interleukin-2

ASJC Scopus subject areas

  • Biochemistry

Cite this

Aurintricarboxylic Acid Blocks in Vitro and in Vivo Activity of YopH, an Essential Virulent Factor of Yersinia pestis, the Agent of Plague. / Liang, Fubo; Huang, Zhonghui; Lee, Seung Yub; Liang, Jiao; Ivanov, Maya I.; Alonso, Andres; Bliska, James B.; Lawrence, David S.; Mustelin, Tomas; Zhang, Zhong-Yin.

In: Journal of Biological Chemistry, Vol. 278, No. 43, 24.10.2003, p. 41734-41741.

Research output: Contribution to journalArticle

Liang, F, Huang, Z, Lee, SY, Liang, J, Ivanov, MI, Alonso, A, Bliska, JB, Lawrence, DS, Mustelin, T & Zhang, Z-Y 2003, 'Aurintricarboxylic Acid Blocks in Vitro and in Vivo Activity of YopH, an Essential Virulent Factor of Yersinia pestis, the Agent of Plague', Journal of Biological Chemistry, vol. 278, no. 43, pp. 41734-41741. https://doi.org/10.1074/jbc.M307152200
Liang, Fubo ; Huang, Zhonghui ; Lee, Seung Yub ; Liang, Jiao ; Ivanov, Maya I. ; Alonso, Andres ; Bliska, James B. ; Lawrence, David S. ; Mustelin, Tomas ; Zhang, Zhong-Yin. / Aurintricarboxylic Acid Blocks in Vitro and in Vivo Activity of YopH, an Essential Virulent Factor of Yersinia pestis, the Agent of Plague. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 43. pp. 41734-41741.
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AU - Ivanov, Maya I.

AU - Alonso, Andres

AU - Bliska, James B.

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AU - Mustelin, Tomas

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