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Unc119 protects from Shigella infection by inhibiting the Abl family kinases.

Vepachedu R, Karim Z, Patel O, Goplen N, Alam R - PLoS ONE (2009)

Bottom Line: We employed loss-of-function and gain-in-function approaches to study the effect of Unc119 in a mouse model of pulmonary shigellosis.Conversely, Unc119 knockdown in vivo results in enhanced bacterial invasion and increased lethality.Unc119 is an inducible protein.

View Article: PubMed Central - PubMed

Affiliation: National Jewish Health, Denver, CO, USA.

ABSTRACT

Background: Bacteria engage cell surface receptors and intracellular signaling molecules to enter the cell. Unc119 is an adaptor protein, which interacts with receptors and tyrosine kinases. Its role in bacterial invasion of cells is unknown.

Methodology/principal findings: We used biochemical, molecular and cell biology approaches to identify the binding partners of Unc119, and to study the effect of Unc119 on Abl family kinases and Shigella infection. We employed loss-of-function and gain-in-function approaches to study the effect of Unc119 in a mouse model of pulmonary shigellosis. Unc119 interacts with Abl family kinases and inhibits their kinase activity. As a consequence, it inhibits Crk phosphorylation, which is essential for Shigella infection. Unc119 co-localizes with Crk and Shigella in infected cells. Shigella infectivity increases in Unc119-deficient epithelial and macrophage cells. In a mouse model of shigellosis cell-permeable TAT-Unc119 inhibits Shigella infection. Conversely, Unc119 knockdown in vivo results in enhanced bacterial invasion and increased lethality. Unc119 is an inducible protein. Its expression is upregulated by probacteria and bacterial products such as lipopolysacharide and sodium butyrate. The latter inhibits Shigella infection in mouse lungs but is ineffective in Unc119 deficiency.

Conclusions: Unc119 inhibits signaling pathways that are used by Shigella to enter the cell. As a consequence it provides partial but significant protection from Shigella infections. Unc119 induction in vivo boosts host defense against infections.

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A schematic presentation of the action of select Shigella-derived effector proteins on the host cell and the mechanism of inhibition of Shigella invasion by Unc119.
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pone-0005211-g008: A schematic presentation of the action of select Shigella-derived effector proteins on the host cell and the mechanism of inhibition of Shigella invasion by Unc119.

Mentions: In summary, Shigella infection elicits two opposing signaling events (Figure 8). Through the activation of tyrosine kinases and Rho/Rac family of GTPases it induces actin polymerization and cytoskeletal reorganization, which promotes its own uptake. Shigella also recruits Unc119 through CD44, which inhibits Abl/Arg tyrosine kinases and Crk phosphorylation. This leads to an inhibition of bacterial uptake. Shigella stimulates Unc119 synthesis, which further boosts this inhibitory pathway. We speculate that this Unc119-mediated inhibition represents a non-immunologic recovery mechanism in certain infections.


Unc119 protects from Shigella infection by inhibiting the Abl family kinases.

Vepachedu R, Karim Z, Patel O, Goplen N, Alam R - PLoS ONE (2009)

A schematic presentation of the action of select Shigella-derived effector proteins on the host cell and the mechanism of inhibition of Shigella invasion by Unc119.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2667249&req=5

pone-0005211-g008: A schematic presentation of the action of select Shigella-derived effector proteins on the host cell and the mechanism of inhibition of Shigella invasion by Unc119.
Mentions: In summary, Shigella infection elicits two opposing signaling events (Figure 8). Through the activation of tyrosine kinases and Rho/Rac family of GTPases it induces actin polymerization and cytoskeletal reorganization, which promotes its own uptake. Shigella also recruits Unc119 through CD44, which inhibits Abl/Arg tyrosine kinases and Crk phosphorylation. This leads to an inhibition of bacterial uptake. Shigella stimulates Unc119 synthesis, which further boosts this inhibitory pathway. We speculate that this Unc119-mediated inhibition represents a non-immunologic recovery mechanism in certain infections.

Bottom Line: We employed loss-of-function and gain-in-function approaches to study the effect of Unc119 in a mouse model of pulmonary shigellosis.Conversely, Unc119 knockdown in vivo results in enhanced bacterial invasion and increased lethality.Unc119 is an inducible protein.

View Article: PubMed Central - PubMed

Affiliation: National Jewish Health, Denver, CO, USA.

ABSTRACT

Background: Bacteria engage cell surface receptors and intracellular signaling molecules to enter the cell. Unc119 is an adaptor protein, which interacts with receptors and tyrosine kinases. Its role in bacterial invasion of cells is unknown.

Methodology/principal findings: We used biochemical, molecular and cell biology approaches to identify the binding partners of Unc119, and to study the effect of Unc119 on Abl family kinases and Shigella infection. We employed loss-of-function and gain-in-function approaches to study the effect of Unc119 in a mouse model of pulmonary shigellosis. Unc119 interacts with Abl family kinases and inhibits their kinase activity. As a consequence, it inhibits Crk phosphorylation, which is essential for Shigella infection. Unc119 co-localizes with Crk and Shigella in infected cells. Shigella infectivity increases in Unc119-deficient epithelial and macrophage cells. In a mouse model of shigellosis cell-permeable TAT-Unc119 inhibits Shigella infection. Conversely, Unc119 knockdown in vivo results in enhanced bacterial invasion and increased lethality. Unc119 is an inducible protein. Its expression is upregulated by probacteria and bacterial products such as lipopolysacharide and sodium butyrate. The latter inhibits Shigella infection in mouse lungs but is ineffective in Unc119 deficiency.

Conclusions: Unc119 inhibits signaling pathways that are used by Shigella to enter the cell. As a consequence it provides partial but significant protection from Shigella infections. Unc119 induction in vivo boosts host defense against infections.

Show MeSH
Related in: MedlinePlus