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THE YERSINIA YSC-YOP

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Title: THE YERSINIA YSC-YOP


1
  • THE YERSINIA YSC-YOP TYPE III WEAPONRY
  • G.R. Cornelis, 2002. Nature Reviews
  • in Molecular Cell Biology 3 742-752.

2
TYPE III SECRETION
  • What is it?
  • Why is it important?
  • Who does it?

3
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.

4
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.

5
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.

6
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.

7
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.
8
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.

9
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!

10
From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
11
YOPS EFFECTS
  • Phagocyte paralysis
  • Reduction in pro-inflammatory response
  • Inhibition of lymphocyte proliferation

12
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.

13
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.

14
From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
15
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.

16
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.

17
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.

18
From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
19
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.

20
From Cornelis, G.R., 2002. Yersinia Type III
secretion send in the effectors. Journal of
Cell Biology 158 (3) 401-408.
21
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.

22
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