My lab is interested in elucidation the activity of virulence factors (also called effectors) from pathogenic bacteria so that we can gain novel molecular insight into eukaryotic signaling systems.
Virulence factors are secreted by bacterial using a type III secretion system (T3SS) resembling a needle-like structure that efficiently translocates virulence factors from bacteria into the cytosol of a host cell. The virulence factors have evolved in a manner similar to many of the viral oncogenes; a eukaryotic activity is usurped and modified by the pathogen for its own advantage.
Studies in my lab focused on YopJ, a bacterial effector expressed by Yersinia. This pathogen, the causal agent of the Plague, uses YopJ to shut down the signaling machinery responsible for eliciting an immune response. We discovered that YopJ uses a novel post-translational modification, Ser/Thr acetylation to modify kinases and prevent their activation by phosphorylation (Science. 323:269-272, 2009).
Genomic sequencing of Vibrio parahaemolyticus revealed the existence of two pathogenicity islands that encode both a T3SS and putative effectors. The first pathogenicity island contains T3SS1 and is associated with cytotoxicity. We have demonstrated that the V. parahaemolyticus uses T3SS1 to orchestrate a multifaceted host cell infection by induction of autophagy, cell rounding and then cell lysis (PNAS (USA) 105:12497-12502, 2008). Recently, we attributed the cell rounding phenotype to VopS, an effector that AMPylates the Rho family of GTPases thereby preventing them from interacting with downstream signaling molecules. We are analyzes the contribution of other effectors in this cytotoxic process (Science. 312:1211-1214, 2006).
The second pathogenicity island of Vibrio parahaemolyticus contains T3SS2 and is associated with an enterotoxicity. We have identified the activity of two effectors on this island. The first, VopA, is a homologue of Yersinia YopJ and also displays acetylatransferase activity (J. Biol. Chem. 282: 34299-34305, 2007). Another effector, VopL, during infection promotes the assembly of actin stress fibers and in vitro, recombinant VopL potently induces assembly of actin filaments that grow at their barbed ends, independent of eukaryotic factors (PNAS USA 104: 17117-17122, 2007).
We are working on T3SS systems and bacterial effectors to understand how signaling systems in the eukaryotic host can be manipulated by bacterial pathogens. These studies provide novel insight into the molecular workings of eukaryotic signal transduction. Our work at UT Southwestern is accomplished using a broad range of tools, including biochemistry, molecular microbiology, protein chemistry, structural biology, yeast genetics, cell biology and more.
RESEARCH INTERESTS
Biochemistry
Molecular Microbiology
Cellular Signaling
RECENT PUBLICATIONS
1. Yarbrough, M., Li, Y., Kinch, L.N., Grishin, N.V., Hall B.E., & Orth, K., "AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling." Science, 323:269-272, January 2009
Laskowski-Arce, M.A. and Orth, K., "A molecular conversation between a protozoan predator and a food-borne bacterial pathogen." Applied and Environmental Microbiology, 74:7183-7188, 2008
Burdette, D., Yarbrough, M., Orvedahl, A., Gilpin, C. & Orth, K., "Vibrio parahaemolyticus orchestrates a multifaceted host cell infection by induction of autophagy, cell rounding and then cell lyses." PNAS USA, 105:12497-12502, 2008
Hao, Y-H., Wang, Y., Burdette, D., Mukherjee, S., Keitany, G., Goldsmith, E., and Orth, K., "Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways." PLoS ONE, 1:1-9, 2008
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
SIGNIFICANT PUBLICATIONS
Yarbrough, M., Li, Y., Kinch, L.N., Grishin, N.V., Hall B.E., & Orth, K., "AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling." Science, 323:269-272, January 2009
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
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
Trosky, J. E., Li, Y., Mukherjee, S., Keitany, G., Ball, H. and Orth, K., "VopA Inhibits ATP binding by Acetylating the Catalytic Loop of MKKs." J. Biol. Chem., 282:34299-34305, 2007
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