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?

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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


Salmonella chaperone proteins

Salmonella chaperone proteins


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


Who cares about rho gtpases

Fig. 1. Rho GTPases are targets for bacterial virulence factors.


Fig 2 bacterial virulence factors affect spatial and temporal regulation of rho

Fig. 2. Bacterial virulence factors affect spatial and temporal regulation of Rho.


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.


Fig 3 virulence factors can adapt or mimic eukaryotic mechanisms

Fig. 3. Virulence factors can adapt or mimic eukaryotic mechanisms.


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


Fig 4 domain organization of virulence factors activating or inhibiting rho gtpases

Fig. 4. Domain organization of virulence factors activating or inhibiting Rho GTPases.


Fig 5 mechanisms to transfer rho virulence factors into the cell cytosol

Fig. 5. Mechanisms to transfer Rho virulence factors into the cell cytosol.


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?


The end

The End


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