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THE YERSINIA YSC-YOP ‘TYPE III’ WEAPONRY G.R. Cornelis, 2002. Nature Reviews

THE YERSINIA YSC-YOP ‘TYPE III’ WEAPONRY G.R. Cornelis, 2002. Nature Reviews in Molecular Cell Biology 3: 742-752. TYPE III SECRETION. What is it? Why is it important? Who does it?. TYPE III SECRETION.

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THE YERSINIA YSC-YOP ‘TYPE III’ WEAPONRY G.R. Cornelis, 2002. Nature Reviews

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  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.

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