The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of in Neutrophils.

The type IV secretion system (-T4SS) of exploits specific cellular carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), such as CEACAM1, -3, -5, and -6, as cellular receptors for CagA translocation into human gastric epithelial cells. We studied the interaction of with human CEACAM1, CEACAM3, and CEACAM6 receptors (hCEACAMs) expressed on myeloid cells from CEACAM-humanized mice. Human and CEACAM-humanized mouse polymorphonuclear neutrophils (PMNs) allowed a specific HopQ-dependent interaction strongly enhancing CagA translocation.

Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3.

The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-κB signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed -deficient mice, which develop hypertrophic lymph nodes.

Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation.

Translocation of the Helicobacter pylori (Hp) cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV Secretion System (cag-T4SS) into host cells is a hallmark of infection with Hp and a major risk factor for severe gastric diseases, including gastric cancer. To mediate the injection of CagA, Hp uses a membrane-embedded syringe-like molecular apparatus extended by an external pilus-like rod structure that binds host cell surface integrin heterodimers. It is still largely unclear how the interaction of the cag-T4SS finally mediates translocation of the CagA protein into the cell cytoplasm.

Migrating Platelets Are Mechano-scavengers that Collect and Bundle Bacteria.

Blood platelets are critical for hemostasis and thrombosis and play diverse roles during immune responses. Despite these versatile tasks in mammalian biology, their skills on a cellular level are deemed limited, mainly consisting in rolling, adhesion, and aggregate formation. Here, we identify an unappreciated asset of platelets and show that adherent platelets use adhesion receptors to mechanically probe the adhesive substrate in their local microenvironment.

Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA.

Helicobacter pylori (Hp) strains that carry the cag type IV secretion system (cag-T4SS) to inject the cytotoxin-associated antigen A (CagA) into host cells are associated with peptic ulcer disease and gastric adenocarcinoma. CagA translocation by Hp is mediated by β1 integrin interaction of the cag-T4SS. However, other cellular receptors or bacterial outer membrane adhesins essential for this process are unknown.

Characterization of Helicobacter pylori VacA-containing vacuoles (VCVs), VacA intracellular trafficking and interference with calcium signalling in T lymphocytes.

The human pathogen Helicobacter pylori colonizes half of the global population. Residing at the stomach epithelium, it contributes to the development of diseases such as gastritis, duodenal and gastric ulcers, and gastric cancer. A major factor is the secreted vacuolating toxin VacA, which forms anion-selective channels in the endosome membrane that cause the compartment to swell, but the composition and purpose of the resulting VacA-containing vacuoles (VCVs) are still unknown.

Helicobacter pylori interferes with leukocyte migration via the outer membrane protein HopQ and via CagA translocation.

The human gastric pathogen Helicobacter pylori is a paradigm for chronic bacterial infections. Persistent colonization of the stomach mucosa is facilitated by several mechanisms of immune evasion and immune modulation, such as avoidance of Toll-like receptor recognition or skewing of effector T cell responses. Interactions of H.

Freedom and constraint in engineered noncolinear polyketide assembly lines.

Many pharmacologically important natural products are assembled by modular type I polyketide synthases (PKS), which typically act in a unidirectional fashion. The synthases producing the unusual nitro-substituted polyketides neoaureothin (nor, also called spectinabilin) and aureothin (aur) are exceptional, as they employ individual modules iteratively. Here, we investigate the plasticity of the nor PKS and the factors governing the number of elongations catalyzed by the noncanonical module.

Vinylogous chain branching catalysed by a dedicated polyketide synthase module.

Bacteria use modular polyketide synthases (PKSs) to assemble complex polyketides, many of which are leads for the development of clinical drugs, in particular anti-infectives and anti-tumoral agents. Because these multifarious compounds are notoriously difficult to synthesize, they are usually produced by microbial fermentation. During the past two decades, an impressive body of knowledge on modular PKSs has been gathered that not only provides detailed insight into the biosynthetic pathways but also allows the rational engineering of enzymatic processing lines to yield structural analogues.

Pyran formation by an atypical CYP-mediated four-electron oxygenation-cyclization cascade in an engineered aureothin pathway.

Small changes, big effect: A new aureothin derivative, aureopyran, which features an unusual pyran backbone, was generated by simply altering the enzymatic methylation topology. The α-pyrone ring hampers the correct placement of the polyketide backbone in the multifunctional cytochrome P450 monooxygenase AurH. Instead of a tetrahydrofuran ring, an oxo intermediate is formed that readily undergoes a rare electrocyclization reaction.

Interchenar retrotransfer of aureothin intermediates in an iterative polyketide synthase module.

The course of the enigmatic iterative use of a polyketide synthase module was deduced from targeted domain inactivation in the aureothin assembly line. Mutational analyses revealed that the N-terminus of AurA is not involved in the iteration process, ruling out an ACP-ACP shuttle. Furthermore, an AurA(KS°, ACP°)-AurA(AT(0)) heterodimer proved to be nonfunctional, whereas aureothin production was restored in a ΔaurA mutant complemented with AurA(KS°)-AurA(ACP°).

Structural characterization of two lipopolysaccharide O-antigens produced by the endofungal bacterium Burkholderia sp. HKI-402 (B4).

Two different polysaccharides were isolated and identified from the lipopolysaccharide fraction of endofungal bacterium Burkholderia sp. HKI-402 (B4). The complete structure was elucidated by chemical analysis and 2D NMR spectroscopy as the following:

Exploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues.

Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring, and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation, and combinatorial biosynthesis, a defined library of aureothin analogues was generated.

Evolution of metabolic diversity in polyketide-derived pyrones: using the non-colinear aureothin assembly line as a model system.

Polyketide-derived pyrones are structurally diverse secondary metabolites that are represented in all three kingdoms of life and are endowed with various biological functions. The aureothin family of Streptomyces metabolites was chosen as a model to study the factors governing structural diversity and the evolutionary processes involved. This review highlights recent insights into the non-colinear aureothin and neoaureothin modular type I polyketide synthase (PKS), aromatic starter unit biosynthesis, polyketide tailoring reactions, and a non-enzymatic polyene splicing cascade.

Polyketide-chain branching by an enzymatic Michael addition.

A new "branch" for polyketide synthases was discovered in the biosynthesis of the antimitotic rhizoxin complex in the endofungal bacterium Burkholderia rhizoxinica. Genetic engineering and the structural elucidation of pathway intermediates revealed that a complex polyketide chain is branched at the beta position by an unprecedented conjugate addition of an acetyl building block to an acryloyl precursor (see scheme).

Eschar with cellulitis as a clinical predictor in community-acquired methicillin-resistant Staphylococcus aureus (MRSA) skin abscess.

This study was designed to determine the validity of a central eschar with surrounding cellulitis as a clinical predictor for CA-MRSA infection. In this 10-month prospective observational study, patients with a chief complaint or clinical findings of skin infection with abscess had study data sheets placed on their chart. All abscesses were treated with incision and drainage, and wound cultures were obtained.