THE YERSINIA YSC-YOP

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• THE YERSINIA YSC-YOP TYPE III WEAPONRY
• G.R. Cornelis, 2002. Nature Reviews
• in Molecular Cell Biology 3 742-752.

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TYPE III SECRETION

• What is it?
• Why is it important?
• Who does it?

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TYPE III SECRETION

• Bacteria inject proteins across cellular
  membranes into the host cell cytosol that have
  complex effects on intracellular systems.
• Type III secretion systems (TTSS) are found in a
  variety of animals, plants, and insects but the
  evolution is unclear.
• TTSS are often plasmid-encoded.

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Yersinia TTSS

• Yops Yersinia outer proteins
• Ysc Yop secretion apparatus
• Effectors Yops that enter the host cell and
  alter host cell functioning.
• Injectisome bacterial organelle that secretes
  the effector proteins into the host cell.

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Yersinia TTSS Overview

• Yersinia adhere to cell surface and deliver Yops
  into host cell cytosol with injectisome.
• Yops functions
• 1) cytoskeletal effects interfere with
  phagocytosis.
• 2) inhibit production of cytokines, chemokines,
  and adhesion molecules.
• Yersinia are better able to survive and multiply
  in lymphoid tissues by using the TTSS.

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Yops

• Translocator Yops
• YopB, YopD, LcrV form the pore for delivery.
• Effector Yops
• YopH, YopE, YopT, YpkA/YopO cytoskeletal
  disturbances, inhibition of phagocytosis.
• YopP downregulation of inflammatory response.
• YopM function uncertain.

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INJECTISOME

• Basal body with protein pump (YscN) and a central
  pore (YscC).
• Needle-like projection (YscF) for Yops delivery.

From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
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INJECTISOME

• Translocator YopB, YopD, LcrV are required to
  form pores for cell delivery.
• Some Yops require chaperone proteins.
• YopN, TyeA, LcrG plug the injectisome channel
  before Yops delivery to cell.
• Cell adhesion required for injectisome function.

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INJECTISOME

• Does the injectisome needle pierce the host
  cell membrane, retract, or break down?
• Maybe translocator Yops destabilize host cell
  membranes after adhesion to allow piercing?
• Once the pore is formed, even non-effector
  proteins can be delivered to the host cell!

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From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
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YOPS EFFECTS

• Phagocyte paralysis
• Reduction in pro-inflammatory response
• Inhibition of lymphocyte proliferation

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PHAGOCYTE PARALYSIS

• Synergistic effects of Yops H, E, T, and O.
• YopH a phosphotyrosine phosphotase (PTPase)
• Dephosphorylates focal adhesion protein p130.
• Dephosphoylates scaffolding proteins SKAP-HOM.
• Suppresses oxidative burst in macrophages.
• Reduces calcium signals needed for phagocytosis.

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PHAGOCYTE PARALYSIS

• YopE a GTPase activating protein (GAP) that
  hydrolyzes Rho, Rac, Cdc42 to off position.
• YopT a cysteine protease that inactivates Rho,
  Rac, Cdc42 by cleaving from plasma membrane.
• YpkA/YopO an autophosphorylating
  serine/threonine kinase that inhibits Rho and Rac
  by an unknown mechanism.

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From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
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INHIBITING INFLAMMATION

• YopP possibly a SUMO protease.
• Inhibits the IKKB that would phosphorylate IKB to
  release inhibition of NF-KB. Because NF-KB is
  inhibited, PMN recruitment decreases due to
• Decreased TNF release by macrophages.
• Decreased IL-8 release from epithelial and
  endothelial cells.
• Decreased ICAM and E-selectin adhesion molecule
  expression on endothelial cells.

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INHIBITING INFLAMMATION

• Other YopP effects
• Inhibition of MAPK kinases that keep the CREB
  transcription factor from being activated.
• Induction of macrophage apoptosis by cleavage of
  the Bcl-2 protein Bid, release of cytochrome c
  from mitochondria, and activation of caspases.

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INHIBITING INFLAMMATION

• YopH in addition to antiphagocytic activities
• Inhibition of the PI3K/Akt pathway, causing
• Reduced MCP1 synthesis that is needed to recruit
  macrophages to lymph nodes.
• Reduced T cell ability for cytokine production.
• Reduced B cell ability to upregulate surface
  costimulatory molecules such as CD86.

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From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
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MYSTERIOUS YOPS

• YopM important virulence factor in mice.
• Subunits form a hollow cylinder.
• Uses a vesicle associated pathway to migrate to
  cell nucleus and inhibit transcription of genes
  involved in cell growth and proliferation.
• LcrV in addition to translocation of Yops
• Promotes IL-10 production that suppresses TNF
  production in macrophages.
• IL-10 deficient mice are more resistant to
  Yersinia infection but mechanisms are difficult
  to study.

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From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
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CONCLUSIONS

• Translocator Yops B, D, LcrV.
• Effector Yops Yop H, E, T, O, P, M.
• Yersinia Ysc-Yop TTSS has complex effects
• Inhibition of phagocytosis.
• Reduced recruitment of PMNs and macrophages.
• Inhibition of lymphocyte proliferation.

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