<i>Chlamydia trachomatis</i>‐derived deubiquitinating enzymes in mammalian cells during infection

Misaghi, Shahram; Balsara, Zarine R.; Catic, André; Spooner, Eric; Ploegh, Hidde L.; Starnbach, Michael N.

doi:10.1111/j.1365-2958.2006.05199.x

Cited by 135 publications

(141 citation statements)

References 34 publications

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“…Even though this finding may support previous studies demonstrating that CD4 T cells are the main effectors for the control of Chlamydia infection (44), the rarity of class I peptides was somewhat unexpected as Chlamydia is known to secrete proteins into the vacuolar membrane and host cytosol (45). The low abundance of class I peptides might be due to the presence of recently identified Chlamydia-encoded deubiquitinating enzymes that are speculated to reduce proteasome generation of antigenic peptides for class I presentation (46). Other possible reasons might include the lack of consensus motif sequences or proteolytic cleavage sites in secreted Chlamydia proteins, low-affinity interactions with MHC, or synthesis at time points in the Chlamydia developmental cycle not assessed in this study.…”

Section: Discussioncontrasting

confidence: 34%

Immunoproteomic Discovery of Novel T Cell Antigens from the Obligate Intracellular Pathogen Chlamydia

Karunakaran

Rey-Ladino

Stoynov

et al. 2008

The Journal of Immunology

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*Chlamydia infections cause substantial morbidity worldwide and effective prevention will depend on a vaccine. Since Chlamydia immunity is T cell-mediated, a major impediment to developing a molecular vaccine has been the difficulty in identifying relevant T cell Ags. In this study, we used a combination of affinity chromatography and tandem mass spectrometry to identify 13 Chlamydia peptides among 331 self-peptides presented by MHC class II (I-A b ) molecules from bone marrow-derived murine dendritic cells infected with Chlamydia muridarum. These MHC class II-bound peptides were recognized by Chlamydia-specific CD4 T cells harvested from immune mice and adoptive transfer of dendritic cells pulsed ex vivo with the peptides partially protected mice against intranasal and genital tract Chlamydia infection. The results provide evidence for lead vaccine candidates for a T cell-based subunit molecular vaccine against Chlamydia infection suitable for human study. The Journal of Immunology, 2008, 180: 2459 -2465. W orld-wide Chlamydia trachomatis is annually responsible for Ͼ92 million sexually transmitted infections and 85 million ocular infections (1). Public health programs have targeted C. trachomatis as a major problem because the organism causes long-term sequelae such as infertility, ectopic pregnancy, and blindness. Sexually transmitted C. trachomatis is also a potent cofactor facilitating the transmission of HIV (2) and interacts with oncogenic human papilloma virus in the pathogenesis of cervical neoplasia (3). In developed countries, public health measures to control Chlamydia are failing as case rates continue to rise, perhaps due to early antibiotic treatment interfering with the acquisition of immunity (4); these approaches to control Chlamydia are not feasible for much of the developing world. Thus, a new approach, such as an effective vaccine, is needed if Chlamydia control is to be achieved in the developing and developed world.Previous vaccine research using inactivated Chlamydia bacterial cells demonstrated partial short-term protection which may have been complicated by immunopathology during breakthrough infection (5). These vaccine trials yielded important lessons for the modern era of Chlamydia vaccinology, namely, that an effective Chlamydia vaccine will need to be molecularly defined and engender long-lived protective immune responses. Immunity to C. trachomatis is now known to depend on cell-mediated immune (CMI) 3 responses, especially Th1-polarized cytokine responses (6). Abs appear to play a secondary role (7). Experience has shown that developing vaccines for intracellular pathogens that require protective CMI is more difficult than for pathogens that simply require protective Ab (8). Part of the problem has been the identification of Ags that induce CMI responses because such Ags need to be presented to T cells by MHC molecules, and identifying MHC-bound microbial epitopes has been notoriously difficult (6). Since T cell responses mainly recognize protein Ags, protective vaccine candida...

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Section: Discussioncontrasting

confidence: 34%

Immunoproteomic Discovery of Novel T Cell Antigens from the Obligate Intracellular Pathogen Chlamydia

Karunakaran

Rey-Ladino

Stoynov

et al. 2008

The Journal of Immunology

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“…Further sequence analysis revealed that the last SENP family member, SENP8, which removes Nedd8 modifications, also lacks this phenylalanine residue and that it instead has a glutamine residue at this position (2). Sequence analysis of two deubiquitinating enzymes that were recently characterized from Chlamydia trachomatis showed that, in place of the conserved phenylalanine from Ulp1 and SENP family members, there is also a glutamine residue at this position (2,39). The finding that deubiquitinating enzymes and deneddylating enzymes lack the phenylalanine residue of Ulp1 and SENPs further supports the notion that this phenylalanine residue may play a role in Smt3 and M-SUMO recognition.…”

Section: Substrate Specificity Of Xopd-previous Results Showing Thatmentioning

confidence: 99%

Structural Analysis of Xanthomonas XopD Provides Insights into Substrate Specificity of Ubiquitin-like Protein Proteases

Chosed

Tomchick

Brautigam

et al. 2007

Journal of Biological Chemistry

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XopD (Xanthomonas outer protein D), a type III secreted effector from Xanthomonas campestris pv. vesicatoria, is a desumoylating enzyme with strict specificity for its plant small ubiquitin-like modifier (SUMO) substrates. Based on SUMO sequence alignments and peptidase assays with various plant, yeast, and mammalian SUMOs, we identified residues in SUMO that contribute to XopD/SUMO recognition. Further predictions regarding the enzyme/substrate specificity were made by solving the XopD crystal structure. By incorporating structural information with sequence alignments and enzyme assays, we were able to elucidate determinants of the rigid SUMO specificity exhibited by the Xanthomonas virulence factor XopD.The small ubiquitin-like modifier (SUMO) 2 is a member of a large family of reversible post-translational modifiers. SUMO is structurally similar to ubiquitin. Like ubiquitin, SUMO utilizes a conjugation machinery (ubiquitin-activating enzyme, ubiquitin carrier protein, and ubiquitin-protein isopeptide ligase) to modify target proteins, but sumoylated proteins are not targeted for degradation by the proteasome (1). The conjugation machinery catalyzes the formation of a covalent isopeptide bond between the C-terminal glycine residue of SUMO and the ⑀-amino group of a lysine residue in the target protein. The removal of SUMO moieties from conjugated proteins by isopeptidases regenerates pools of processed SUMOs and unmodified target proteins.

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“…The role of CPAF in immune evasion in vivo remains to be determined. Another class of factors that may play a role in evading T cells are the deubiquitinases (DUBs) encoded by C. trachomatis (Misaghi et al 2006). The functions of Chlamydia DUBs are unknown, but it is attractive to speculate that the removal of ubiquitin from Chlamydia proteins by the DUBs may interfere with targeting of these proteins to the proteasome.…”

Section: Immune Evasion By C Trachomatismentioning

confidence: 99%

Immune-mediated control of Chlamydia infection

Roan

Starnbach²

2007

Cell Microbiol

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SummaryInfection with the bacterium Chlamydia trachomatis can lead to a variety of diseases, including ectopic pregnancy, infertility and blindness. Exposure of the host to C. trachomatis stimulates multiple innate and adaptive immune effectors that can contribute towards controlling bacterial replication. However, these effectors are often insufficient to resolve the infection and prevent re-infection, and the continued presence of C. trachomatis within the host may induce immune effectors to chronically produce inflammatory cytokines. This may eventually lead to the tissue pathologies associated with the infection. Reducing the incidence and sequelae of infection will ultimately require the development of a C. trachomatis vaccine that can stimulate sterilizing immunity while avoiding immune-mediated pathology.

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Chlamydia trachomatis‐derived deubiquitinating enzymes in mammalian cells during infection

Cited by 135 publications

References 34 publications

Immunoproteomic Discovery of Novel T Cell Antigens from the Obligate Intracellular Pathogen Chlamydia

Immunoproteomic Discovery of Novel T Cell Antigens from the Obligate Intracellular Pathogen Chlamydia

Structural Analysis of Xanthomonas XopD Provides Insights into Substrate Specificity of Ubiquitin-like Protein Proteases

Immune-mediated control of Chlamydia infection

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