takehome3 - Question 1A: Compare the methods used by four...

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Question 1A: Compare the methods used by four different bacteria we have discussed in this class to alter the activity of Rho family members. The Rho family of GTPases is a family of small signaling G protein. Members of the Rho GTPase family regulate manyaspects of intracellular actin dynamics. Rho/Rac are involved in cellular functions such as cell polarity, movement (via filopodia, lamellipodia), phagocytosis and transcriptional dynamics. The ability to modify central host cellular function is a major advantage for many bacterial pathogens. Yersin ia spp. is one bacterium that can alter the activity of Rho family members. Pathogenic yersiniae employ a type III secretion system for translocation effector proteins into the eukaryotic cell. Yersinia modulates the activity of Rho GTP-binding proteins both for tissue invasion and subversion of the host immune system. Rho family members RhoA, Rac1 and Cdc42 are activated by invasin- triggered integrin signaling and mediate cytoskeletal reorganization, IL-8 release and bacterial invasion YopT, cystein proteins removes the C-terminal isoprenoid group of Rho A, Rac, CDC42H. By cleaving RhoA, RhoA is removed from the membrane, leading to an increase in its inactive RhoGDI-bound form and depolymerizing actin (Aepfelbacher et al., 2003). YopO/YpKa inhibit Rac1 and RhoA via a domain that is structurally similar to the guanine nucleotide dissociation inhibitors for Rho GTPases. YopO binds to RhoA and thus inhibits signaling from Gαq proteins (Navarro et al, 2007). YopE mimics a GTPase activating protein (GAP) to downregulate Rac1, RhoA, and CDC42 in infected cells. YopE catalyzes the conversion of active GTP bound form of RhoA and Rac1 into their inactive GDP bound form. This causes the destruction of actin stress fibers, preventing macrophages and neutrophils from phagocytosing the Yersinia bacterium (Pawel-Rammingen et al., 2002). These three Yops are important in virulence because they target Rho family proteins to disrupt actin cytoskeleton. (See Figure 1)
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Figure 1 YopE GAP inactivates Rac and Cdc42 while YopT modifies RhoA, destryoing stress fibers. Clostridium difficile can also alter Rho in the host cell. Two major virulence factor of C. difficile are glucosylating exotoxins A and B (TcdA and TcdB), single chain proteins with multiple domains for receptor binding and enzymatic activity located on the PaLoc pathogenicity island (Voth and Ballard, 2005). Toxin A and B are homologous to glucosynltransferase that monoglucoslyate Rho GTPases. Both toxins enter the target host cell by forming pores. They translocate the N-terminal catalytic domains into the cytosol of the host cell and inactivate Rho guanosine triphosphatases by glucoslyation. After binding their receptors, exotoxins A and B are endocytosed. Acidification of the toxins in endosome exposes the hydrophobic regions of the proteins to allow their insertion into the membrane. Toxins A and B target RhoA, B, C, Rac 1-3, RhoG, Cdc42, and TC10, and not Rho E and RhoD (Jank et al., 2007). Toxin A and B modify
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takehome3 - Question 1A: Compare the methods used by four...

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