Type III secretion systems

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Type III secretion systems

• Professor Mark Pallen
• University of Birmingham

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Bacterial Secretion Systems
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Type-III secretion systems

• Similar systems described in range of human,
  animal and plant pathogens

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Type III Secretion Systems

• Yersinia spp. Ysc system
• secretes Yops
• Locus for enterocyte effacement (LEE)
• Enteropathogenic E. coli
• Enterohaemorrhagic E. coli
• secretes EspA, B, D
• Salmonella typhimurium
• SPI1, SPI2
• secrete Sips and Sops etc

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Type III Secretion Systems

• Plant pathogens
• Secretes harpins, avirulence proteins
• Pseudomonas aeruginosa
• Secretes ExoS
• Chlamydia spp.
• Secretion targets unknown
• Rhizobium meliloti megaplasmid
• Secretion targets unknown

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TTSSs Five Functions

• Export proteins across bacterial cell envelope
• Bring bacterial and host cells close together
• Translocate proteins between bacterial and host
  cells
• Translocate proteins across host cell membrane
• Translocated protaiens subvert host cell functions

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TTSSs Five Components

• Regulators
• Chaperones
• Secretion apparatus
• Translocation apparatus
• Effector proteins

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Regulation of secretion
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TTSS chaperones

• Type III secretion depends on cytosolic molecular
  chaperones
• bind specifically to the translocators and
  effectors
• chaperone loss results in rapid degradation,
  aggregation or reduced secretion of its cognate
  secretion substrate(s)
• Sequence identity low but common features
• similar small size (100-150 residues)
• C-terminal amphipathic helix
• tendency towards an acidic pI
• 4 structures (SicP, SycE, SigE, CesT) reported
• All from chaperones of multiple effectors class

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Tetratricopeptide repeats (TPRs)

• imperfect 34-amino-acid repeat
• often arranged in tandem arrays
• sequence is poorly conserved
• similar residue types found at canonical
  positions
• originally identified as a protein-protein
  interaction domain in yeast cell-cycle proteins
• act as interaction modules in eukaryotic systems
• signal transduction pathways
• protein transport across membranes (e.g. in the
  peroxisome and mitochondrial import complexes)
• molecular chaperone complexes involving HSP70 and
  HSP90
• co-chaperones use TPRs to bind HSPs

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TPRs define a new class of TTSS
translocator-chaperones
Also found in HilA-like regulators and other TTSS
regulators
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Needle complexComparison with the Flagellum
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TTSSs Extra-cellular Organelles

• Invasome and needles in Salmonella
• Hrp pilus in Pseudomonas syringae
• EspA pilus in EPEC

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The EspA Pilus
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The EspA Pilus
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Flagellar Biosynthesis
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A Molecular Syringe?
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Cellular subversion by TTSSs

• Cytoskeletal and surface changes
• Membrane ruffling
• AE lesion formation (Tir translocation)
• Invasion
• Activation of host cell signal transduction
  pathways
• Vesicular trafficking
• Triggering apoptosis
• Suppression of TNF-a production

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Activities of effector proteins

• ExoS, SptP, YopE have ADP-ribosylase domains
• SptP and YopH have PTPase domains
• YpkA is a Ser/Thr kinase

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Targets of effector proteins

• IpaB binds to interleukin-1beta converting enzyme
  (ICE)
• IpaA binds to vinculin
• AvrPto binds to Pto kinase
• p130Cas and FAK are substrates for YopH
• P. aeruginosa exoenzyme S ADP-ribosylates Ras at
  multiple sites

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Subversion of signalling

• Yersinia inhibits NF-KB synthesis, downregulates
  MAP kinases p38 and JNK
• CDC42 required for Salmonella-induced
  cytoskeletal and nuclear responses
• S. typhimurium stimulates of MAP kinase signaling
  pathways.
• SptP disrupts the actin cytoskeleton.

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EPEC effectors
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TTSSs Summary

• Type III Secretion Systems are multi-protein
  complexes connecting bacteria to host cells
• Mediate protein secretion and translocation from
  bacterial cytoplasm to host cell interior
• Effector proteins subvert cellular functions
• Therefore, important not just to bacterial
  pathogenesis, but to the wider field of
  eucaryotic cell biology.

Bacteria are excellent cell biologists Stanley
Falkow