Who cares about Rho GTPases?

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Who cares about Rho GTPases?. Clostridium spp. Salmonella spp. Bordetella spp. Neisseria spp. http://www.geocities.com/CapeCanaveral/3504/gallery.htm. Historical GTPase Events. 1985 isolation of Rho = R as ho molog - PowerPoint PPT Presentation


<ul><li><p>Who cares about Rho GTPases?http://www.geocities.com/CapeCanaveral/3504/gallery.htmBordetella spp.Neisseria spp.Clostridium spp.Salmonella spp.</p></li><li><p>Historical GTPase Events1985 isolation of Rho = Ras homolog</p><p>1989 C3 transferase shown to inactivate RhoC =&gt; actin disruption in host cells. Isolation of Rac = Ras substrate of C3.</p><p>1990s Rho/Rac GTPases shown to act as switches to control membrane receptors and actin cytoskeleton plasticity.</p></li><li><p>Salmonella entericaType III Secretion System (TTSS) for translocation of virulence factors</p><p>http://info.med.yale.edu/micropath/galan/Pages/galan_overview.html</p></li><li><p>Salmonella chaperone proteins</p></li><li><p>after effector translocationBacterial changes: transient bacterial invasome appendagesHost cell changes: macropinocytosis for uptake of Salmonella in nonphagocytic cellsbacterial induced apoptosis in phagocytic cells.</p></li><li><p>Salmonella invasion summaryhttp://info.med.yale.edu/micropath/galan/Pages/galan_overview.html</p></li><li><p>Bacterial StrategiesRHO FAMILY GTPASES: Rho, Rac, Cdc42BACTERIAL INHIBITION OF RHO PROTEINS:-Large clostridial toxins: Toxin A, B, Lethal Toxin -C. botulinum C3 transferase-Salmonella SptP, Yersinia YopE</p><p>BACTERIAL ACTIVATION OF RHO PROTEINS:-E.coli CNF1 and 2 Toxins-Bordetella dermonecrotizing toxin (DNT) -Salmonella SopE, Yersinia CNFY</p></li><li><p>Fig. 1. Rho GTPases are targets for bacterial virulence factors.</p></li><li><p>Fig. 2. Bacterial virulence factors affect spatial and temporal regulation of Rho.</p></li><li><p>Why target Rho GTPases?Invasion can be dangerous!Innate immunity recognize non-self and opsonize for phagocytic cell recognition. LPS recognized by TLRs stimulates NF-KB and leads to transcription of antibacterial factors.Cell shedding removes adhered bacteria.Adaptive immunity takes time.</p><p>Virulence factors help microbes invade on their own terms! Rho GTPases are key.</p></li><li><p>Fig. 3. Virulence factors can adapt or mimic eukaryotic mechanisms.</p></li><li><p>How do virulence factors enter?ToxinsCan act distantly to bacteria because all required elements for virulence self-contained.Diptheria A-B example:A region catalytically active, delivered to cytosol.B region for binding host cell and translocating the A-enzymatic fragment to host cytosol at low pH.</p><p>Type III or IV Secretion Systems</p></li><li><p>Fig. 4. Domain organization of virulence factors activating or inhibiting Rho GTPases.</p></li><li><p>Fig. 5. Mechanisms to transfer Rho virulence factors into the cell cytosol.</p></li><li><p>Rho InhibitorsClassical model:Toxins effects were irreversible, while TTSS induced reversible changes in Rho.Large clostridial toxins (LCTs)Toxins A, B, Lethal Toxin.Type Three Secretion SystemsPseudomonas ExoS, ExoT.Salmonella SptP, Yersinia YopT, YopE.C3 transferases, YopT: spatial regulation.</p></li><li><p>Rho activatorsE.coli CNF, Bordetella DNF:Block RhoGAP activity so GTPase is permanently active until ubiquitinylation and proteosomal degradation.Is proteosomal degradation of overactivated Rho a cellular defense that microbes are taking advantage of?</p><p>Salmonella SopE, E2:Rho GEF function to activate Rho but is counterbalanced by SptP GAP activity.</p></li><li><p>Fig. 5. Comparison of activation-deactivation of Rac by Salmonella SopE/Sptp and E. coli CNF1.</p></li><li><p>Why activation/deactivation?Whether the bacteria supplies the Rho counterbalance (Salmonella) to virulence or the host cell provides it (E.coli) </p><p>-is it simply to return to normal cell function? </p><p>-or to enhance bacterial uptake?-or to avoid non-physiologic cell environs that prevent bacterial uptake at all?</p></li><li><p>SummaryRho GTPases can be influenced by:</p><p>Activities from separate bacterial factorsSalmonella SopE, SptP; Yersinia YopE,YopTDual activity factorsPseudomonas ExoS, ExoTSingle activity proteinsE. coli CNF1 Toxin</p><p>What is the future of the host-pathogen interaction? Extremes vs balance?</p></li><li><p>The End</p></li></ul>