Requirement for the Rac GTPase in <i>Chlamydia trachomatis</i> Invasion of Non‐phagocytic Cells

Carabeo, Rey A.; Grieshaber, Scott S.; Hasenkrug, Aaron M.; Dooley, Cheryl A.; Hackstadt, Ted

doi:10.1111/j.1398-9219.2004.00184.x

Cited by 88 publications

(117 citation statements)

References 48 publications

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“…TARP multimerization likely occurs in the host cell after translocation through the type III secretion system, because complexes Ͼ800 kDa, the observed size of oligomerized TARP peptide (200 aa) by gel filtration are too large for secretion. TARP complexes in vitro appear to be stable; however, it is possible that complex formation in vivo is more transient given the dynamic regulation of actin recruitment and pedestal formation associated with EB internalization (5,27).…”

Section: Discussionmentioning

confidence: 99%

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Chlamydial TARP is a bacterial nucleator of actin

Jewett¹,

Fischer

Mead³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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172

224

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Chlamydia trachomatis entry into host cells results from a parasitedirected remodeling of the actin cytoskeleton. A type III secreted effector, TARP (translocated actin recruiting phosphoprotein), has been implicated in the recruitment of actin to the site of internalization. To elucidate the role of TARP in actin recruitment, we identified host cell proteins that associated with recombinant GST-TARP fusions. TARP directly associated with actin, and this interaction promoted actin nucleation as determined by in vitro polymerization assays. Domain analysis of TARP identified an actin-binding domain that bears structural and primary amino acid sequence similarity to WH2 domain family proteins. In addition, a proline-rich domain was found to promote TARP oligomerization and was required for TARP-dependent nucleation of new actin filaments. Our findings reveal a mechanism by which chlamydiae induce localized cytoskeletal changes by the translocated effector TARP during entry into host cells.Chlamydia ͉ type III secretion ͉ cytoskeleton ͉ endocytosis A Gram-negative obligate intracellular bacterium, Chlamydia trachomatis, is the leading cause of preventable blindness worldwide and the most prevalent bacterial pathogen causing sexually transmitted disease in the western world (1). Chlamydiae initiate their intracellular developmental cycle by actively gaining entry into host cells. The extracellular infectious form of the developmental cycle is referred to as an elementary body (EB). Once engulfed by the host cell, the EB differentiates into the replicative reticulate body within the protective confines of a membrane-bound parasitophorous vacuole called an inclusion (2).The ligands on the EB surface and cognate host cell receptor have not been definitively identified; however, it appears that chlamydiae use an entry mechanism that involves several distinct levels of interaction (3, 4). EB invasion of nonphagocytic cells is thus the product of coordinated cytoskeletal remodeling characterized by the formation of pedestal-like structures and hypertrophic microvilli that are directly triggered by the invading chlamydiae (5).A recently identified C. trachomatis type III secretion system secreted protein called TARP (for translocated actin recruiting phosphoprotein) is tyrosine-phosphorylated by a host cell kinase and is spatially and temporally associated with the recruitment of actin at the site of EB invasion (6). TARP is present in all pathogenic Chlamydia species examined to date. Analysis of TARP orthologs from C. trachomatis, Chlamydia muridarium, Chlamydia caviae, and Chlamydia pneumoniae indicates that only C. trachomatis serovars are phosphorylated, despite all Chlamydia strains demonstrating the recruitment of actin to the site of entry (6, 7).We demonstrate here that TARP associates directly with actin by a small domain contained within the C-terminal region of the protein. Furthermore, TARP independently nucleates new actin filaments by forming a large homogenous multimeric protein complex mediated by a prolin...

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Section: Discussionmentioning

confidence: 99%

“…The Rho family GTPase, Rac, is activated and required for C. trachomatis entry, whereas both Rac and Cdc42 appear to be required for C. caviae internalization (27,41). Rac activation is associated with lamellipodia formation in a process that involves WAVE2 and Arp2͞3 (23).…”

Section: Discussionmentioning

confidence: 99%

Chlamydial TARP is a bacterial nucleator of actin

Jewett¹,

Fischer

Mead³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

172

224

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“…For bacteria like group B Streptococcus and Vibrio parahaemolyticus, all three Rac, Cdc42 and Rho GTPases are involved in cell invasion [28,29]. In contrast, Chlamydia trachomatis requires solely Rac for internalization [30]. In other cases, a combination of two GTPases allows invasion, as in the case of Candida albicans that needs Rho and Rac to modulate actin cytoskeleton organization [31].…”

Section: Discussionmentioning

confidence: 99%

Rck of Salmonella enterica, subspecies enterica serovar Enteritidis, mediates Zipper-like internalization

et al. 2010

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Salmonella can invade non-phagocytic cells through its type III secretion system (T3SS-1), which induces a Trigger entry process. This study showed that Salmonella enterica, subspecies enterica serovar Enteritidis can also invade cells via the Rck outer membrane protein. Rck was necessary and sufficient to enable non-invasive E. coli and Rckcoated beads to adhere to and invade different cells. Internalization analysis of latex beads coated with different Rck peptides showed that the peptide containing amino acids 140-150 promoted adhesion, whereas amino acids between 150 and 159 modulated invasion. Expression of dominant-negative derivatives and use of specific inhibitors demonstrated the crucial role of small GTPases Rac1 and Cdc42 in activating the Arp2/3 complex to trigger formation of actin-rich accumulation, leading to Rck-dependent internalization. Finally, scanning and transmission electron microscopy with Rck-coated beads and E. coli expressing Rck revealed microvillus-like extensions that formed a Zipper-like structure, engulfing the adherent beads and bacteria. Overall, our results provide new insights into the Salmonella T3SS-independent invasion mechanisms and strongly suggest that Rck induces a Zipper-like entry mechanism. Consequently, Salmonella seems to be the first bacterium found to be able to induce both Zipper and Trigger mechanisms to invade host cells.

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“…Rac1 is required for C. trachomatis entry (Carabeo et al 2004), whereas Cdc42 and Arf6 are also required for Chlamydophila caviae internalization Balana et al 2005). Rac1 activation results in the recruitment of the actin regulators WAVE2, Abi-1, and Arp2/ 3, which are necessary for C. trachomatisinduced actin reorganization (Carabeo et al 2007).…”

Section: Mechanisms Of Chlamydia Invasion Of Epithelial Cellsmentioning

confidence: 99%

Chlamydial Intracellular Survival Strategies

Bastidas

Elwell

Engel

et al. 2013

Cold Spring Harbor Perspectives in Medicine

207

197

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Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen and the causative agent of blinding trachoma. Although Chlamydia is protected from humoral immune responses by residing within remodeled intracellular vacuoles, it still must contend with multilayered intracellular innate immune defenses deployed by its host while scavenging for nutrients. Here we provide an overview of Chlamydia biology and highlight recent findings detailing how this vacuole-bound pathogen manipulates host -cellular functions to invade host cells and maintain a replicative niche.

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Requirement for the Rac GTPase in Chlamydia trachomatis Invasion of Non‐phagocytic Cells

Cited by 88 publications

References 48 publications

Chlamydial TARP is a bacterial nucleator of actin

Chlamydial TARP is a bacterial nucleator of actin

Rck of Salmonella enterica, subspecies enterica serovar Enteritidis, mediates Zipper-like internalization

Chlamydial Intracellular Survival Strategies

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