who cares about rho gtpases?
DESCRIPTION
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 PresentationTRANSCRIPT
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Who cares about Rho GTPases?
http://www.geocities.com/CapeCanaveral/3504/gallery.htm
Bordetella spp. Neisseria spp.
Clostridium spp.
Salmonella spp.
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Historical GTPase Events
• 1985 – isolation of Rho = ‘Ras homolog’
• 1989 – C3 transferase shown to inactivate RhoC => actin disruption in host cells. Isolation of Rac = ‘Ras substrate of C3’.
• 1990’s – Rho/Rac GTPases shown to act as switches to control membrane receptors and actin cytoskeleton plasticity.
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Salmonella enterica
Type III Secretion System (TTSS) for translocation of virulence factors
http://info.med.yale.edu/micropath/galan/Pages/galan_overview.html
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Salmonella chaperone proteins
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…after effector translocation…Bacterial changes: transient bacterial ‘invasome’ appendages
Host cell changes: macropinocytosis for uptake of Salmonella in nonphagocytic cells
bacterial induced apoptosis in phagocytic cells.
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Salmonella invasion summary
http://info.med.yale.edu/micropath/galan/Pages/galan_overview.html
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Bacterial StrategiesRHO FAMILY GTPASES: Rho, Rac, Cdc42
BACTERIAL INHIBITION OF RHO PROTEINS:
-Large clostridial toxins: Toxin A, B, Lethal Toxin
-C. botulinum C3 transferase
-Salmonella SptP, Yersinia YopE
BACTERIAL ACTIVATION OF RHO PROTEINS:
-E.coli CNF1 and 2 Toxins
-Bordetella dermonecrotizing toxin (DNT)
-Salmonella SopE, Yersinia CNFY
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Fig. 1. Rho GTPases are targets for bacterial virulence factors.
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Fig. 2. Bacterial virulence factors affect spatial and temporal regulation of Rho.
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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.
• Virulence factors help microbes invade on their own terms! Rho GTPases are key.
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Fig. 3. Virulence factors can adapt or mimic eukaryotic mechanisms.
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How do virulence factors enter?
• Toxins– Can 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.
• Type III or IV Secretion Systems
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Fig. 4. Domain organization of virulence factors activating or inhibiting Rho GTPases.
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Fig. 5. Mechanisms to transfer Rho virulence factors into the cell cytosol.
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Rho Inhibitors
• Classical model:– Toxins effects were irreversible, while TTSS
induced reversible changes in Rho.
• Large clostridial toxins (LCTs)– Toxins A, B, Lethal Toxin.
• Type Three Secretion Systems– Pseudomonas ExoS, ExoT.– Salmonella SptP, Yersinia YopT, YopE.
• C3 transferases, YopT: spatial regulation.
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Rho activators• E.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?
• Salmonella SopE, E2:– Rho GEF function to activate Rho but is
counterbalanced by SptP GAP activity.
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Fig. 5. Comparison of activation-deactivation of Rac by Salmonella SopE/Sptp and E. coli CNF1.
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Why activation/deactivation?
• Whether the bacteria supplies the Rho counterbalance (Salmonella) to virulence or the host cell provides it (E.coli)…
-is it simply to return to ‘normal’ cell function?
-or to enhance bacterial uptake?
-or to avoid non-physiologic cell environs that prevent bacterial uptake at all?
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Summary• Rho GTPases can be influenced by:
– Activities from separate bacterial factors• Salmonella SopE, SptP; Yersinia YopE,YopT
– Dual activity factors• Pseudomonas ExoS, ExoT
– Single activity proteins• E. coli CNF1 Toxin
• What is the future of the host-pathogen interaction? Extremes vs balance?
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The End