Chapter 1 : Type III Secretory Proteins in

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is a normal inhabitant of soil and water and is ubiquitous in the environment. Importantly, uses additional bacterial products encoded by the T3SS to directly deliver enzymes into cells to alter host physiology. This chapter summarizes the discovery, molecular properties, and host cofactors of the T3SS-delivered enzymes of . The first identified T3SS effector, exoenzyme S (ExoS), was actually discovered before the components of the secretory system in were known. The data argues that ExoS traffics within host cells and that some of the biological consequences of ExoS delivery may be related to its localization. The chapter focuses on the biological and biochemical implications of the need for eukaryotic cofactors for bacterial toxin activity by using the studies of the enzymatic activity of ExoU as a paradigm. The T3SS and the effector proteins encoded by provide model systems for fundamental studies of host-pathogen relationships and the expression of virulence factors relative to the pathological consequences of infection. The opportunistic nature of infections suggests that the acquisition and maintenance of the genes encoding the T3SS provide the bacterium with a selective advantage in the environment. The identification of cofactors that are ubiquitous in eukaryotic organisms but not present or active in prokaryotes and the linkage to type III secretion may reveal unique mechanisms to ensure the specific targeting of the toxin.

Citation: Sato H, Frank D. 2007. Type III Secretory Proteins in , p 3-22. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch1

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Type III Secretion System
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Functional domains in type III effector proteins. encodes four enzymes, ExoS, ExoT, ExoY, and ExoU, that are injected into eukaryotic cells by the T3SS. Important functional domains, denoted by boxes with amino acid sequence boundaries, are shown. ExoS and ExoT contain MLDs and require R146 and R149 for GAP activity and E381 and E383 for ADP-ribosyltransferase (ADP-r) activity, respectively. The sequence DALDL (amino acids 424 to 428) in ExoS is critical for 14-3-3 cofactor binding. Two conserved regions in ExoY, an ATP-GTP binding motif and a β- and γ-phosphate interaction motif (PIM), align with corresponding regions of other bacterial adenylyl cyclases, CyaA () and EF (). The N-terminal half of ExoU contains residues for a PLA catalytic dyad, S142 and D344, and a glycine-rich motif (GXSXG, amino acids 111 to 116 [where X represents any residue]). The C-terminal (C-term) domain of ExoU is also important for enzymatic activity and may contain sequences required for cofactor binding, the recognition of membrane substrates, ubiquitinylation, or localization. The N-terminal regions of all four enzymes contain sequences required for type III secretion and binding sites for their respective cognate chaperone proteins (data not shown).

Citation: Sato H, Frank D. 2007. Type III Secretory Proteins in , p 3-22. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch1
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Image of FIGURE 2

ExoU damages host membranes in vivo. A control strain expressing β-galactosidase demonstrates smooth vacuolar morphology with Nomarski interference microscopy (bottom left panel). Quinacrine staining generally reveals a single vacuole and few acidic vesicles (top left panel). Strains expressing ExoU (5 h of induction; right panels) demonstrate a vacuole fragmentation phenotype (numerous acidic vesicles). These data suggest that ExoU-mediated vacuolar fragmentation is due to the breakdown of vacuoles and not a failure of vacuolar biogenesis.

Citation: Sato H, Frank D. 2007. Type III Secretory Proteins in , p 3-22. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch1
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Image of FIGURE 3

The preincubation of rExoU with yeast extract does not accelerate enzyme activation. rExoU (1 µg) was preincubated with 2.5 µg of yeast extract for 30 min (solid squares), followed by the addition of radiolabeled liposomes. Phospholipase activity levels were measured after 1, 2, and 3 h of incubation at 30°C. The kinetics of substrate (1-palmitoyl-2-oleoylphosphatidylcholine [POPC] hydrolysis after preincubation were similar to those of a control with no preincubation (0 min, open triangles).

Citation: Sato H, Frank D. 2007. Type III Secretory Proteins in , p 3-22. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch1
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Image of FIGURE 4

Noncatalytic forms of rExoU compete with the wild-type enzyme. Wild-type (WT) rExoU (2.5 µg; 33.8 pmol) and 5 µg of yeast soluble extract were used in the competition studies. The following noncatalytic forms of rExoU were added to the reaction mixture: 343-687U (gray squares), an rExoU mutant with a truncation of the N-terminal domain, and S142A (solid diamonds), a form of rExoU with a site-specific alanine substitution at the serine catalytic site. rPcrV (open triangles), a T3SS-secreted protein, was used as a negative control. Phospholipase activity levels are represented as percentages of the positive control (the activity level of wild-type rExoU) at various molar ratios of a competitor of the wild-type enzyme. The phospholipase activity of the wild-type enzyme was inhibited more than 90% by S142A and 70% by 343-687U, suggesting that the noncatalytic molecules compete with the wild-type enzyme for a common cofactor.

Citation: Sato H, Frank D. 2007. Type III Secretory Proteins in , p 3-22. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch1
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