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Phylogeny of the mucosal immune system
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Robert D. Miller, Irene Salinas
The evolution of different classes of immunoglobulins has occurred through both gene duplication and gene reorganization. In the bony fish and the tetrapods (amphibians, birds, reptiles, and mammals), the immunoglobulin (Ig) genes are organized in what is termed a “translocon” arrangement. The translocon arrangement is generally a single heavy-chain locus with clusters of separate variable (V), diversity (D), and joining (J) segments upstream of the exons encoding the constant domains. The significance of this translocon arrangement is that it facilitated the specialization of different antibody heavy-chain isotypes through gene duplication, ultimately leading to the evolution of different isotypes, such as IgG and the mucosa-associated antibodies IgT, IgX, and IgA (see Table 2.1). The evolution of class switching, however, did not drive isotype diversification, because multiple antibody classes are also found in cartilaginous fishes (sharks, rays, and skates) as well as bony fishes. However, class switching was a significant evolutionary innovation because it allowed B cells to change the functional attributes of the secreted antibody without changing antigen specificity.
Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
In human bronchial epithelial cells (HBECs), it was shown that amplifiers increased levels of immature F508del-CFTR more than the mature form (67). F508del-CFTR mRNA levels present at the ER were higher upon amplifier treatment, but to maintain this increase of CFTR, mRNA active translation was required (71). The first transmembrane domain (TM1) of CFTR acts as an inefficient signal sequence, which reduces effective membrane targeting for translation (72). In silico modeling of charged residues-to-alanine mutations residing in TM1, combined with in vitro experiments, demonstrated a lack of PTI-CH effectivity in these mutants (71). In the current model, PTI-428 and PTI-CH function by enhancing successful signal-sequence targeting of CFTR to the signal recognition particle (SRP), which in turn targets the ribosome-nascent chain complex to the translocon in the ER membranes for synthesis of the immature CFTR protein (69,71,73).
Engineering Escherichia coli to Combat Cancer
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Carlos Piñero-Lambea, David Ruano-Gallego, Gustavo Bodelón, Beatriz Álvarez, Luis Ángel Fernández
When the basal needle complex of EPEC injectisomes is assembled, it mediates the secretion of the translocator proteins EspB, EspD, and EspA. EspA forms the extracellular filaments that extend up to 700 nm from the basal complex of the injectisome. EspB and EspD get located on the tip of EspA filaments and later form the translocon pore in the plasma membrane of the mammalian cell for injection of proteins (reviewed in Ref. [94]). Bacteria expressing a functional needle complex are able to secrete EspA, EspB, and EspD proteins. Analysis of the proteins found in the culture media of IPTG-induced SIEC strain allowed the detection of EspA, EspB, and EspD (Fig. 7.5B). Importantly, in the absence of an inducer, the proteins EspB, EspD, and EspA were not efficiently secreted by SIEC. Likewise, the strain SIECΔp1 was defective for the secretion of EspA, EspB, and EspD proteins. In addition, assembly of EPEC injectisomes in the SIEC strain was also supported by visualization of EspA filaments on the surface of induced SIEC bacteria using electron microscopy. Injectisomes could be purified and visualized by electron microscopy from the induced SIEC strain as well as the wild-type EPEC (Fig. 7.5C).
Protein misfolding, ER stress and chaperones: an approach to develop chaperone-based therapeutics for Alzheimer’s disease
Published in International Journal of Neuroscience, 2023
Rimaljot Singh, Navpreet Kaur, Neelima Dhingra, Tanzeer Kaur
ER serves as a primary site for the synthesis of secretory and integral membrane proteins[33] along with a couple of cytosolic proteins [34]. The proper functioning of proteins depends on the post-translational modifications, folding, and assembly of newly synthesized proteins. While translation continues in ER, the emerging proteins are translocated into the ER lumen via a proteinaceous pore called the translocon [35]. Once the proteins are translocated, the nascent proteins start to acquire secondary, tertiary, or quaternary structures along with several post-translational modifications including the addition of glycans, disulfide bond formation, oligomerization, proteolytic cleavage, or other processes. Most of these events are initiated inside the ER with the aid of ER-resident folding enzymes and chaperones, among them certain chaperones are calcium-dependent such as calreticulin, calnexin, GRP78, and GRP94) [36–38]. Regulation of Ca2+ ions concentration is essential for the efficient working of various molecular pathways of the cell. GRP94 is extensively responsible for the maintenance of cellular Ca2+ homeostasis [38]. Additionally, these chaperones are responsible for carrying out numerous functions including retaining proteins in a folding-competent state, catalyzing isomerization reactions, preventing secretory pathways to transport luminal protein, and regulating the degradation of misfolded proteins via a process called ERAD (ER-associated degradation) mechanism [39].
SPI2 T3SS effectors facilitate enterocyte apical to basolateral transmigration of Salmonella-containing vacuoles in vivo
Published in Gut Microbes, 2021
Marcus Fulde, Kira van Vorst, Kaiyi Zhang, Alexander J. Westermann, Tobias Busche, Yong Chiun Huei, Katharina Welitschanski, Isabell Froh, Dennis Pägelow, Johanna Plendl, Christiane Pfarrer, Jörn Kalinowski, Jörg Vogel, Peter Valentin-Weigand, Michael Hensel, Karsten Tedin, Urska Repnik, Mathias W. Hornef
In order to more specifically address the role of the SPI2 T3SS during enterocyte egress and exclude an influence of the surrounding tissue on the observed phenotype, we employed a reductionist approach using highly polarized murine small intestinal epithelial m-ICcl2 cells grown on transwell filter inserts. Enterocyte invasion by S. Typhimurium in this model is SPI1 T3SS-dependent as illustrated by significantly reduced numbers of intraepithelial SPI1 T3SS mutant ΔinvC S. Typhimurium in the classical gentamicin kill assay (Fig. S1H and I). Consistent with the in vivo phenotype (Figure 1(c)), deletion of the SPI2 T3SS translocon component SseB or the ATPase SsaN required for SPI2 T3SS-mediated effector molecule translocation did not alter intraepithelial survival and growth (Fig. S1J and K). Notably, the absence of a functional SPI2 T3SS significantly reduced the bacterial egress at the basolateral plasma membrane (Figure 4(d-e)) and this difference was not explained by an altered cell viability (Fig. S1L).18,26 Thus, a functional SPI2 T3SS was dispensable for intraepithelial survival but required for epithelial m-ICcl2 cell egress. Consistently, wt S. Typhimurium were identified in the lamina propria close to the epithelial layer in vivo (Fig. S2).
Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis
Published in Tissue Barriers, 2020
Alistair Taverner, Julia MacKay, Floriane Laurent, Tom Hunter, Keyi Liu, Khushdeep Mangat, Lisa Song, Elbert Seto, Sally Postlethwaite, Aatif Alam, Apurva Chandalia, Minji Seung, Mazi Saberi, Weijun Feng, Randall J. Mrsny
Cholix (Chx) is composed of a single chain of 643 amino acids that folds into domains designated as Ia, II, Ib, and III; this order reflects its folded organization with relation to its N- to C-terminus orientation.11 Chx can intoxicate nonpolarized cells through a mechanism that involves several steps: 1) receptor-mediated endocytosis, 2) furin cleavage at position R292, 3) retrograde vesicular trafficking to the endoplasmic reticulum (ER) facilitated by a C-terminal KDEL amino acid sequence, and 4) transfer of amino acids 293–643 to the cell cytoplasm through a mechanism that may involve the Sec61 translocon.12 These steps are considered essential to the presumed virulence function of Chx that involves cytoplasmic delivery of an enzymatic activity within domain III of the protein that ADP-ribosylates cytoplasmic elongation factor 2 to suppress protein synthesis to induce apoptosis. To date, Chx structure/function studies have focused on how this exotoxin intoxicates nonpolarized cells such as those that would be present in the lamina propria of the intestinal mucosa as a way to stabilize nonpandemic V. cholerae in the intestinal lumen.11,13 At present, the mechanism(s) by which Chx can reach these cells following secretion from luminal V. cholerae is unclear. Herein, we present several key findings related to the apical to basal (A→B) transcytosis mechanism used by Chx to reach nonpolarized cells within the lamina propria.