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Chlamydial entry involves TARP binding of guanine nucleotide exchange factors.

Lane BJ, Mutchler C, Al Khodor S, Grieshaber SS, Carabeo RA - PLoS Pathog. (2008)

Bottom Line: The Rac GTPase is also activated, resulting in WAVE2 and Arp2/3-dependent recruitment of actin to the sites of chlamydia attachment.The first and second tyrosine residues, when phosphorylated, are utilized by the Sos1/Abi1/Eps8 and Vav2, respectively, with the latter requiring the lipid phosphatidylinositol 3,4,5-triphosphate.Depletion of these critical signaling molecules by siRNA resulted in inhibition of chlamydial invasion to varying degrees, owing to a possible functional redundancy of the two pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Louisville Medical School, Louisville, Kentucky, USA.

ABSTRACT
Chlamydia trachomatis attachment to cells induces the secretion of the elementary body-associated protein TARP (Translocated Actin Recruiting Protein). TARP crosses the plasma membrane where it is immediately phosphorylated at tyrosine residues by unknown host kinases. The Rac GTPase is also activated, resulting in WAVE2 and Arp2/3-dependent recruitment of actin to the sites of chlamydia attachment. We show that TARP participates directly in chlamydial invasion activating the Rac-dependent signaling cascade to recruit actin. TARP functions by binding two distinct Rac guanine nucleotide exchange factors (GEFs), Sos1 and Vav2, in a phosphotyrosine-dependent manner. The tyrosine phosphorylation profile of the sequence YEPISTENIYESI within TARP, as well as the transient activation of the phosphatidylinositol 3-kinase (PI3-K), appears to determine which GEF is utilized to activate Rac. The first and second tyrosine residues, when phosphorylated, are utilized by the Sos1/Abi1/Eps8 and Vav2, respectively, with the latter requiring the lipid phosphatidylinositol 3,4,5-triphosphate. Depletion of these critical signaling molecules by siRNA resulted in inhibition of chlamydial invasion to varying degrees, owing to a possible functional redundancy of the two pathways. Collectively, these data implicate TARP in signaling to the actin cytoskeleton remodeling machinery, demonstrating a mechanism by which C.trachomatis invades non-phagocytic cells.

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A model of the signaling pathway to the Arp2/3 complex.Rac activation, which is required for chlamydia invasion involves two different guanine nucleotide exchange factors that interact directly (Vav2) or indirectly (Sos1/Abi1/Eps8) with the phosphodomain of the TARP protein.
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ppat-1000014-g006: A model of the signaling pathway to the Arp2/3 complex.Rac activation, which is required for chlamydia invasion involves two different guanine nucleotide exchange factors that interact directly (Vav2) or indirectly (Sos1/Abi1/Eps8) with the phosphodomain of the TARP protein.

Mentions: It has been previously shown that invasion of HeLa cells by C. trachomatis serovar L2 is Rac-dependent, and that WAVE2 and Abi1 are downstream effectors that activate the Arp2/3 complex [9],[10],[32]. Given this requirement for Rac activation during chlamydial invasion, the identification of the relevant Rac GEFs defines a mechanistic pathway of chlamydia invasion at the molecular level. A model of the proposed signaling pathway is shown in Figure 6.


Chlamydial entry involves TARP binding of guanine nucleotide exchange factors.

Lane BJ, Mutchler C, Al Khodor S, Grieshaber SS, Carabeo RA - PLoS Pathog. (2008)

A model of the signaling pathway to the Arp2/3 complex.Rac activation, which is required for chlamydia invasion involves two different guanine nucleotide exchange factors that interact directly (Vav2) or indirectly (Sos1/Abi1/Eps8) with the phosphodomain of the TARP protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2279300&req=5

ppat-1000014-g006: A model of the signaling pathway to the Arp2/3 complex.Rac activation, which is required for chlamydia invasion involves two different guanine nucleotide exchange factors that interact directly (Vav2) or indirectly (Sos1/Abi1/Eps8) with the phosphodomain of the TARP protein.
Mentions: It has been previously shown that invasion of HeLa cells by C. trachomatis serovar L2 is Rac-dependent, and that WAVE2 and Abi1 are downstream effectors that activate the Arp2/3 complex [9],[10],[32]. Given this requirement for Rac activation during chlamydial invasion, the identification of the relevant Rac GEFs defines a mechanistic pathway of chlamydia invasion at the molecular level. A model of the proposed signaling pathway is shown in Figure 6.

Bottom Line: The Rac GTPase is also activated, resulting in WAVE2 and Arp2/3-dependent recruitment of actin to the sites of chlamydia attachment.The first and second tyrosine residues, when phosphorylated, are utilized by the Sos1/Abi1/Eps8 and Vav2, respectively, with the latter requiring the lipid phosphatidylinositol 3,4,5-triphosphate.Depletion of these critical signaling molecules by siRNA resulted in inhibition of chlamydial invasion to varying degrees, owing to a possible functional redundancy of the two pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Louisville Medical School, Louisville, Kentucky, USA.

ABSTRACT
Chlamydia trachomatis attachment to cells induces the secretion of the elementary body-associated protein TARP (Translocated Actin Recruiting Protein). TARP crosses the plasma membrane where it is immediately phosphorylated at tyrosine residues by unknown host kinases. The Rac GTPase is also activated, resulting in WAVE2 and Arp2/3-dependent recruitment of actin to the sites of chlamydia attachment. We show that TARP participates directly in chlamydial invasion activating the Rac-dependent signaling cascade to recruit actin. TARP functions by binding two distinct Rac guanine nucleotide exchange factors (GEFs), Sos1 and Vav2, in a phosphotyrosine-dependent manner. The tyrosine phosphorylation profile of the sequence YEPISTENIYESI within TARP, as well as the transient activation of the phosphatidylinositol 3-kinase (PI3-K), appears to determine which GEF is utilized to activate Rac. The first and second tyrosine residues, when phosphorylated, are utilized by the Sos1/Abi1/Eps8 and Vav2, respectively, with the latter requiring the lipid phosphatidylinositol 3,4,5-triphosphate. Depletion of these critical signaling molecules by siRNA resulted in inhibition of chlamydial invasion to varying degrees, owing to a possible functional redundancy of the two pathways. Collectively, these data implicate TARP in signaling to the actin cytoskeleton remodeling machinery, demonstrating a mechanism by which C.trachomatis invades non-phagocytic cells.

Show MeSH
Related in: MedlinePlus