For example, it has been reported that TLR9 is found on all major murine DC subsets, while the protein is only expressed by pDC in humans [75]

For example, it has been reported that TLR9 is found on all major murine DC subsets, while the protein is only expressed by pDC in humans [75]. 3.3. mucosal tumors specifically when STxB-antigen conjugates are administered via the nasal route. It will also be pointed out how STxB-based vaccines have been shown in preclinical malignancy models to synergize with other therapeutic modalities (immune checkpoint inhibitors, anti-angiogenic therapy, radiotherapy). Finally, we will discuss how molecular aspects such as low immunogenicity, cross-species conservation of Gb3 expression, and lack of toxicity contribute to the competitive positioning of STxB among the different DC targeting methods. STxB thereby appears as GSK 525768A an original and innovative tool for the development of mucosal vaccines in infectious diseases and cancer. bacteria, which produce hemolytic-uremic syndrome, the leading cause of pediatric renal failure [5,6], but which GSK 525768A also poses health risks to adults [7]. Open in a separate window Physique 1 STxB trafficking into cells. Left: Shiga holotoxin molecules are composed of a STxB homopentamer (green) and a catalytic A-subunit (reddish), which are non-covalently associated. STxB binds GSK 525768A to the plasma membrane of target cells via the glycosphingolipid Gb3 (not shown). STxB induces an increment of spontaneous curvature, which upon membrane-mediated clustering of several toxin molecules leads to the formation of endocytic pits from which clathrin-independent service providers are generated for toxin trafficking to early endosomes. From there, the holotoxins are transported via the retrograde trafficking route to the endoplasmic reticulum (ER), via the Golgi apparatus. The catalytic A-subunit is usually then translocated to the cytosol where it inhibits protein biosynthesis by modifying ribosomal RNAs (not shown). Right: In STxB (green)-based vaccines, antigens (blue) are linked via covalent bonds to the vector. The endocytic process then operates as for Shiga holotoxin molecules. While STxB-antigen conjugates also undergo retrograde trafficking (not shown), a small fraction of them escapes from your lumen of endosomes to reach the cytosol (endosomal escape). Here, proteasomes process the antigens to generate antigenic peptides, that are then imported into the lumen of the ER (or of endo/phagosomal processing compartments; not shown) for loading onto MHC class I molecules and subsequent presentation at the plasma membrane to CD8+ T cells. The endocytic and intracellular trafficking of STxB has been analyzed in some detail (Physique 1). At the plasma membrane, STxB reorganizes lipids, including its receptor glycolipid Gb3, in a way such that thin tubular endocytic pits are created [8] by exploiting a specific geometry of Gb3 binding sites on STxB [9] and its capacity to induce an asymmetric GSK 525768A compressive stress onto the membrane leaflet to which it binds [10]. STxB-Gb3 complexes are then clustered by membrane-mediated mechanism, likely including lipid Mouse monoclonal to EPCAM fluctuation causes [11]. This mechanism of building endocytic pits without the need for the conventional clathrin machinery has been termed the glycolipid-lectin (GL-Lect) hypothesis [12,13]. This GL-Lect mechanism GSK 525768A has been suggested to apply also for the structurally related glycolipid-binding B-subunit of cholera toxin [14,15,16]. The toxin-induced tubular endocytic pits then detach by scission from your plasma membrane to form clathrin-independent endocytic service providers [17]. This scission reaction involves the conventional pinchase dynamin [8] and also actin-driven domain name boundary causes [18] and a mechanism that has been termed friction-driven scission in which the pulling of the molecular motor dynein on tubular endocytic pits that are scaffolded by the BAR domain protein endophilin leads to the thinning of their necks and to subsequent detachment [19,20]. The thereby generated clathrin-independent endocytic service providers are then targeted in a SNARE protein-dependent manner to early endosomes [21]. From early endosomes, STxB is usually delivered by retrograde transport to the endoplasmic reticulum, via the Golgi apparatus (examined in [22,23,24]) (Physique 1). From there, the catalytic A-subunit is usually.