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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’

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who cares about rho gtpases
Who cares about Rho GTPases?

Clostridium spp.

Salmonella spp.

Bordetella spp. Neisseria spp.

http://www.geocities.com/CapeCanaveral/3504/gallery.htm

historical gtpase events
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.
salmonella enterica
Salmonella enterica

Type III Secretion System (TTSS) for translocation of virulence factors

http://info.med.yale.edu/micropath/galan/Pages/galan_overview.html

after effector translocation
…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.

salmonella invasion summary
Salmonella invasion summary

http://info.med.yale.edu/micropath/galan/Pages/galan_overview.html

bacterial strategies
Bacterial Strategies

RHO 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

why target rho gtpases
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.
how do virulence factors enter
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
rho inhibitors
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.
rho activators
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.
fig 5 comparison of activation deactivation of rac by salmonella sope sptp and e coli cnf1
Fig. 5. Comparison of activation-deactivation of Rac by Salmonella SopE/Sptp and E. coli CNF1.
why activation deactivation
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?

summary
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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