The causal agent of the bubonic plague is the microbial pathogen Yersinia pestis and, during infection, Yersinia evades phagocytosis, destroys the host defense response, and induces apoptosis in target host cells. These activities are efficiently carried about by a mere half dozen proteins called Yersinia outer proteins or Yops. The Yops mimic the activity of an eukaryoytic protein and use this activity to the pathogen’s advantage to debilitate the target cell. One of these proteins, YopJ, has been shown to not only block cytokine production but also promote apoptosis in the infected target host cell by preventing the activation of the superfamily of MAP Kinase Kinases, thereby, inhibiting both the MAP Kinase signaling pathways and the NFkB pathway. My lab discovered that YopJ uses a simple but elegant mechanism to inhibit the NFkB pathway and all MAPK signaling pathways. We showed that YopJ is an acetyltransferase that prevents the activation of eukaryotic MAPK kinases and IKKbeta by acetylating serine and/or threonine residues on the activation loop of these kinases, thereby preventing their activation by phosphorylation. This novel posttranslation modification of Ser/Thr acetylation directly competes with phosphorylation and attenuates signaling by changing the molecular message transduced by a modified residue. The discovery of Ser/Thr acetylation, as with tyrosine phosphorylation, presents a new paradigm for molecular signaling. Bacterial pathogens, like oncogenic viruses, usurp and mold eukaryotic activities so that they may be used during infection to manipulate signaling machinery in the eukaryotic host. The eukaryotic signaling machinery used for Ser/Thr acetylation, including enzymes, substrates and tools for identification, promises to provide new insights into biological signaling systems. The effector YopJ is one example from the enormous repertoire of bacterial effectors that my lab exploits to discover new mechanisms used to regulate eukaryotic signaling pathways.
My lab is also interested in the mechanisms used by another bacterial pathogen, Vibrio parahaemoylyticus. This pathogen contains two type III secretion systems and dozens of novel effectors. We are uncovering the molecular mechanisms used by this pathogen during infection.
RECENT PUBLICATIONS
Orth, K, "Discovery of Mechanisms used by Type III Effectors" Microbes, 2007
Mukherjee, S., Hao, Y-H., and Orth, K, "New posttranslational modification on Ser/Thr residues by acetylation" Trends in Biochemical Sciences, 32:210-216, April 2007
Chosed, R., Tomchick, D.R., Brautigam, C.A., Machius, M.2, & Orth, K, "Structural analysis of Xanthomonas XopD provides insights into substrate specificity of Ulp1s" J. Biol. Chem, 282:6773-6782, 2007
Chosed, R., Mukherjee, S. & Orth, K, "Impact of regulatory domains on activity and specificity of Arabidopsis thaliana Ulp1s" Biochemical J, 398:521-529, 2006
Trosky, J., Mukherjee, S., Burdette, D., Roberts, M., McCarter, L., Siegel, R. & Orth, K, "Inhibition of MAPK signaling pathways by VopA from Vibrio parahaemolyticus" J. Biol. Chem, 279:51953-51957, 2004
SIGNIFICANT PUBLICATIONS
Yi-Heng Hao,, Yong Wang, Dara Burdette, Sohini Mukherjee, Gladys Keitany, Elizabeth Goldsmith & Kim Orth, "Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways" PLoS ONE, 3(1):e1375, January 2008
Amy D.B. Liverman, Hui-Chun Cheng, Jennifer E. Trosky, Daisy W. Leung, Melanie L. Yarbrough, Dara L. Burdette, Michael K. Rosen and Kim Orth, "Arp2/3 Independent Assembly of Actin by Vibrio Type III Effector VopL" PNAS (USA), 104:43:17117-17122, October 2007
Jennifer E. Trosky, Yan Li, Sohini Mukherjee, Gladys Keitany, Haydn Ball and Kim Orth, "VopA Inhibits ATP binding by Acetylating the Catalytic Loop of MKKs" JBC, 282:47:34299-34305, November 2007
Mukherjee, S. Kietany, G., Li, Y Wang, Y., Hall B.E., Goldsmith, E & Orth, K, "Yersinia YopJ Acetylates and Inhibits Kinase Activation by Preventing Phosphorylation" Science, 312:1211-1214, 2006
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