22

Who cares about Rho GTPases?

  • Upload
    eldora

  • View
    48

  • Download
    0

Embed Size (px)

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 Presentation

Citation preview

Page 1: Who cares about Rho GTPases?
Page 2: Who cares about Rho GTPases?

Who cares about Rho GTPases?

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

Bordetella spp. Neisseria spp.

Clostridium spp.

Salmonella spp.

Page 3: Who cares about Rho GTPases?

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.

Page 4: Who cares about Rho GTPases?

Salmonella enterica

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

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

Page 5: Who cares about Rho GTPases?

Salmonella chaperone proteins

Page 6: Who cares about Rho GTPases?

…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.

Page 7: Who cares about Rho GTPases?

Salmonella invasion summary

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

Page 8: Who cares about Rho GTPases?

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

Page 9: Who cares about Rho GTPases?

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

Page 10: Who cares about Rho GTPases?

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

Page 11: Who cares about 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.

Page 12: Who cares about Rho GTPases?
Page 13: Who cares about Rho GTPases?

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

Page 14: Who cares about Rho GTPases?

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

Page 15: Who cares about Rho GTPases?

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

Page 16: Who cares about Rho GTPases?

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

Page 17: Who cares about Rho GTPases?

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.

Page 18: Who cares about Rho GTPases?

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.

Page 19: Who cares about Rho GTPases?

Fig. 5. Comparison of activation-deactivation of Rac by Salmonella SopE/Sptp and E. coli CNF1.

Page 20: Who cares about Rho GTPases?

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?

Page 21: Who cares about Rho GTPases?

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?

Page 22: Who cares about Rho GTPases?

The End