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

THE THE YERSINIAYERSINIA YSC-YOP YSC-YOP ‘TYPE III’ WEAPONRY‘TYPE III’ WEAPONRY

G.R. Cornelis, 2002. Nature Reviews G.R. Cornelis, 2002. Nature Reviews

in Molecular Cell Biology 3: 742-752.in Molecular Cell Biology 3: 742-752.

TYPE III SECRETIONTYPE III SECRETION

What is it?What is it?

Why is it important?Why is it important?

Who does it?Who does it?

TYPE III SECRETIONTYPE III SECRETION

Bacteria inject proteins across cellular Bacteria inject proteins across cellular membranes into the host cell cytosol that have membranes into the host cell cytosol that have complex effects on intracellular systems.complex effects on intracellular systems.

Type III secretion systems (TTSS) are found Type III secretion systems (TTSS) are found in a variety of animals, plants, and insects but in a variety of animals, plants, and insects but the evolution is unclear.the evolution is unclear.

TTSS are often plasmid-encoded.TTSS are often plasmid-encoded.

YersiniaYersinia TTSS TTSS

Yops – Yersinia outer proteinsYops – Yersinia outer proteins

Ysc – Yop secretion apparatusYsc – Yop secretion apparatus

Effectors – Yops that enter the host cell and alter Effectors – Yops that enter the host cell and alter host cell functioning.host cell functioning.

Injectisome – bacterial organelle that secretes the Injectisome – bacterial organelle that secretes the effector proteins into the host cell.effector proteins into the host cell.

YersiniaYersinia TTSS Overview TTSS Overview

YersiniaYersinia adhere to cell surface and deliver adhere to cell surface and deliver Yops into host cell cytosol with injectisome.Yops into host cell cytosol with injectisome.

Yops functions:Yops functions: 1) cytoskeletal effects interfere with phagocytosis.1) cytoskeletal effects interfere with phagocytosis. 2) inhibit production of cytokines, chemokines, 2) inhibit production of cytokines, chemokines,

and adhesion molecules.and adhesion molecules.

YersiniaYersinia are better able to survive and multiply are better able to survive and multiply in lymphoid tissues by using the TTSS.in lymphoid tissues by using the TTSS.

YopsYops

Translocator Yops:Translocator Yops: YopB, YopD, LcrV form the pore for delivery.YopB, YopD, LcrV form the pore for delivery.

Effector Yops:Effector Yops: YopH, YopE, YopT, YpkA/YopO – cytoskeletal YopH, YopE, YopT, YpkA/YopO – cytoskeletal

disturbances, inhibition of phagocytosis.disturbances, inhibition of phagocytosis. YopP – downregulation of inflammatory response.YopP – downregulation of inflammatory response. YopM – function uncertain.YopM – function uncertain.

INJECTISOMEINJECTISOME

Basal body with protein pump (YscN) and a central Basal body with protein pump (YscN) and a central pore (YscC).pore (YscC).

Needle-like projection (YscF) for Yops delivery.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.


Translocator YopB, YopD, LcrV are required Translocator YopB, YopD, LcrV are required to form pores for cell delivery.to form pores for cell delivery.

Some Yops require chaperone proteins.Some Yops require chaperone proteins.

YopN, TyeA, LcrG plug the injectisome YopN, TyeA, LcrG plug the injectisome channel before Yops delivery to cell.channel before Yops delivery to cell.

Cell adhesion required for injectisome function.Cell adhesion required for injectisome function.


Does the injectisome ‘needle’ pierce the host Does the injectisome ‘needle’ pierce the host cell membrane, retract, or break down?cell membrane, retract, or break down?

Maybe translocator Yops destabilize host cell Maybe translocator Yops destabilize host cell membranes after adhesion to allow piercing?membranes after adhesion to allow piercing?

Once the pore is formed, even non-effector Once the pore is formed, even non-effector proteins can be delivered to the host cell!proteins can be delivered to the host cell!


YOPS EFFECTSYOPS EFFECTS

Phagocyte paralysisPhagocyte paralysis

Reduction in pro-inflammatory responseReduction in pro-inflammatory response

Inhibition of lymphocyte proliferationInhibition of lymphocyte proliferation

PHAGOCYTE PARALYSISPHAGOCYTE PARALYSIS

Synergistic effects of Yops H, E, T, and O.Synergistic effects of Yops H, E, T, and O.

YopH – a phosphotyrosine phosphotase (PTPase)YopH – a phosphotyrosine phosphotase (PTPase) Dephosphorylates focal adhesion protein p130. Dephosphorylates focal adhesion protein p130. Dephosphoylates scaffolding proteins SKAP-HOM.Dephosphoylates scaffolding proteins SKAP-HOM. Suppresses oxidative burst in macrophages.Suppresses oxidative burst in macrophages. Reduces calcium signals needed for phagocytosis.Reduces calcium signals needed for phagocytosis.

PHAGOCYTE PARALYSISPHAGOCYTE PARALYSIS

YopE – a GTPase activating protein (GAP) that YopE – a GTPase activating protein (GAP) that hydrolyzes Rho, Rac, Cdc42 to ‘off’ position.hydrolyzes Rho, Rac, Cdc42 to ‘off’ position.

YopT – a cysteine protease that inactivates Rho, YopT – a cysteine protease that inactivates Rho, Rac, Cdc42 by cleaving from plasma membrane.Rac, Cdc42 by cleaving from plasma membrane.

YpkA/YopO – an autophosphorylating YpkA/YopO – an autophosphorylating serine/threonine kinase that inhibits Rho and Rac serine/threonine kinase that inhibits Rho and Rac by an unknown mechanism.by an unknown mechanism.


INHIBITING INFLAMMATIONINHIBITING INFLAMMATION

YopP – possibly a SUMO protease.YopP – possibly a SUMO protease.

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

expression on endothelial cells.expression on endothelial cells.


Other YopP effects: Other YopP effects:

Inhibition of MAPK kinases that keep the CREB Inhibition of MAPK kinases that keep the CREB transcription factor from being activated.transcription factor from being activated.

Induction of macrophage apoptosis by cleavage of Induction of macrophage apoptosis by cleavage of the Bcl-2 protein Bid, release of cytochrome c the Bcl-2 protein Bid, release of cytochrome c from mitochondria, and activation of caspases.from mitochondria, and activation of caspases.


YopH – in addition to antiphagocytic activities:YopH – in addition to antiphagocytic activities:

Inhibition of the PI3K/Akt pathway, causing: Inhibition of the PI3K/Akt pathway, causing: Reduced MCP1 synthesis that is needed to recruit Reduced MCP1 synthesis that is needed to recruit

macrophages to lymph nodes.macrophages to lymph nodes. Reduced T cell ability for cytokine production.Reduced T cell ability for cytokine production. Reduced B cell ability to upregulate surface Reduced B cell ability to upregulate surface

costimulatory molecules such as CD86.costimulatory molecules such as CD86.


MYSTERIOUS YOPSMYSTERIOUS YOPS

YopM – important virulence factor in mice.YopM – important virulence factor in mice. Subunits form a hollow cylinder.Subunits form a hollow cylinder. Uses a vesicle associated pathway to migrate to cell Uses a vesicle associated pathway to migrate to cell

nucleus and inhibit transcription of genes involved nucleus and inhibit transcription of genes involved in cell growth and proliferation.in cell growth and proliferation.

LcrV – in addition to translocation of Yops:LcrV – in addition to translocation of Yops: Promotes IL-10 production that suppresses TNF Promotes IL-10 production that suppresses TNF

production in macrophages.production in macrophages. IL-10 deficient mice are more resistant to IL-10 deficient mice are more resistant to YersiniaYersinia

infection but mechanisms are difficult to study.infection but mechanisms are difficult to study.


CONCLUSIONSCONCLUSIONS

Translocator Yops – B, D, LcrV.Translocator Yops – B, D, LcrV.

Effector Yops – Yop H, E, T, O, P, M.Effector Yops – Yop H, E, T, O, P, M.

YersiniaYersinia Ysc-Yop TTSS has complex effects: Ysc-Yop TTSS has complex effects: Inhibition of phagocytosis.Inhibition of phagocytosis. Reduced recruitment of PMNs and macrophages.Reduced recruitment of PMNs and macrophages. Inhibition of lymphocyte proliferation.Inhibition of lymphocyte proliferation.

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