Tarp regulates early<i>Chlamydia</i>-induced host cell survival through interactions with the human adaptor protein SHC1

Mehlitz, Adrian; Banhart, Sebastian; Mäurer, André P.; Kaushansky, Alexis; Gordus, Andrew; Zielecki, Julia; MacBeath, Gavin; Meyer, Thomas

doi:10.1084/jem2078oia23

Cited by 5 publications

(7 citation statements)

References 42 publications

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“…SH2 domains found in the host proteome specifically associate with phosphotyrosine-containing polypeptides and are potential Tarp-interacting proteins (29). Recent studies have revealed the ability of phosphorylated Tarp to interact with SHC-1 and PI3K (16,17). Tarp binding to SHC-1 is believed to alter host cell signal transduction cascades that favor host cell survival during early chlamydial development (17).…”

Section: Discussionmentioning

confidence: 99%

“…Tarp contains a C-terminal actin binding and oligomerization domain required for actin nucleation and an N-terminal phosphorylation domain implicated in host cell signaling via association with host-derived proteins, such as phosphoinositide 3-kinase (PI3K) and Src homology 2 (SH2) domain-containing transforming protein 1 (SHC-1) (11,(15)(16)(17). Phosphorylated Tarp peptides have also been shown to immunoprecipitate a complex of proteins containing Sos1 and Vav2, two Rac guanine nucleotide exchange factors thought to participate in WAVE2 and Arp2-Arp3 complex recruitment (16).…”

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confidence: 99%

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Chlamydia trachomatis Tarp Harbors Distinct G and F Actin Binding Domains That Bundle Actin Filaments

Jiwani

Alvarado

Ohr

et al. 2012

Journal of Bacteriology

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All species of Chlamydia undergo a unique developmental cycle that transitions between extracellular and intracellular environments and requires the capacity to invade new cells for dissemination. A chlamydial protein called Tarp has been shown to nucleate actin in vitro and is implicated in bacterial entry into human cells. Colocalization studies of ectopically expressed enhanced green fluorescent protein (EGFP)-Tarp indicate that actin filament recruitment is restricted to the C-terminal half of the effector protein. Actin filaments are presumably associated with Tarp via an actin binding alpha helix that is also required for actin nucleation in vitro, but this has not been investigated. Tarp orthologs from C. pneumoniae, C. muridarum, and C. caviae harbor between 1 and 4 actin binding domains located in the C-terminal half of the protein, but C. trachomatis serovar L2 has only one characterized domain. In this work, we examined the effects of domain-specific mutations on actin filament colocalization with EGFP-Tarp. We now demonstrate that actin filament colocalization with Tarp is dependent on two novel F-actin binding domains that endow the Tarp effector with actin-bundling activity. Furthermore, Tarp-mediated actin bundling did not require actin nucleation, as the ability to bundle actin filaments was observed in mutant Tarp proteins deficient in actin nucleation. These data shed molecular insight on the complex cytoskeletal rearrangements required for C. trachomatis entry into host cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Chlamydia trachomatis Tarp Harbors Distinct G and F Actin Binding Domains That Bundle Actin Filaments

Jiwani

Alvarado

Ohr

et al. 2012

Journal of Bacteriology

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“…At least one early secreted effector, TARP, contributes to bacterial internalization by its ability to directly nucleate actin polymerization through a WH2 actin-binding domain mimic (Jewett et al 2006) and by recruiting the guanine nucleotide exchange factors (GEFs) Sos1 and Vav2, which activate Rac1 and signal to the actin machinery (Carabeo et al 2007;Lane et al 2008). This latter mechanism is only relevant in chlamydial species inwhich the polymorphic TARP gene (Clifton et al 2005) can be targeted for tyrosine phosphorylation by Abl, Src, and Syk kinases (Elwell et al 2008;Jewett et al 2008;Lane et al 2008;Mehlitz et al 2008Mehlitz et al , 2010. Microinjection of cells with antibodies directed to the actin-binding domain of TARP before infection significantly reduces bacterial invasion, providing the most conclusive support for a direct role of TARP in mediating bacterial entry (Jewett et al 2010).…”

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

206

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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“…One important example is the C. trachomatis protein encoded at the CT456 locus and called Tarp (translocated actin-recruiting protein). Tarp functions as a multivalent phosphorylation-dependent signaling hub that is crucial for success in the early phase of chlamydial infection (27) and was recently shown to interact with the human adaptor protein SHC1 (85). Variations in chlamydial Tarp exhibit interesting correlations with particular variations of clinical phenotype (76).…”

Section: Type III Secretionmentioning

confidence: 99%

The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

Xie

Bonner

et al. 2012

Microbiol Mol Biol Rev

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SUMMARY One form of immune evasion is a developmental state called “persistence” whereby chlamydial pathogens respond to the host-mediated withdrawal of l -tryptophan (Trp). A sophisticated survival mode of reversible quiescence is implemented. A mechanism has evolved which suppresses gene products necessary for rapid pathogen proliferation but allows expression of gene products that underlie the morphological and developmental characteristics of persistence. This switch from one translational profile to an alternative translational profile of newly synthesized proteins is proposed to be accomplished by maximizing the Trp content of some proteins needed for rapid proliferation (e.g., ADP/ATP translocase, hexose-phosphate transporter, phosphoenolpyruvate [PEP] carboxykinase, the Trp transporter, the Pmp protein superfamily for cell adhesion and antigenic variation, and components of the cell division pathway) while minimizing the Trp content of other proteins supporting the state of persistence. The Trp starvation mechanism is best understood in the human- Chlamydia trachomatis relationship, but the similarity of up-Trp and down-Trp proteomic profiles in all of the pathogenic Chlamydiaceae suggests that Trp availability is an underlying cue relied upon by this family of pathogens to trigger developmental transitions. The biochemically expensive pathogen strategy of selectively increased Trp usage to guide the translational profile can be leveraged significantly with minimal overall Trp usage by (i) regional concentration of Trp residue placements, (ii) amplified Trp content of a single protein that is required for expression or maturation of multiple proteins with low Trp content, and (iii) Achilles'-heel vulnerabilities of complex pathways to high Trp content of one or a few enzymes.

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Tarp regulates earlyChlamydia-induced host cell survival through interactions with the human adaptor protein SHC1

Cited by 5 publications

References 42 publications

Chlamydia trachomatis Tarp Harbors Distinct G and F Actin Binding Domains That Bundle Actin Filaments

Chlamydia trachomatis Tarp Harbors Distinct G and F Actin Binding Domains That Bundle Actin Filaments

Chlamydial Intracellular Survival Strategies

The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

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