Phylogeny of the mucosal immune system
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
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
Anthony J. Hickey, Heidi M. Mansour in Inhalation Aerosols, 2019
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
Ananda M. Chakrabarty, Arsénio M. Fialho in Microbial Infections and Cancer Therapy, 2019
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].
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.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland
Published in Renal Failure, 2019
S. Cormican, D. M. Connaughton, C. Kennedy, S. Murray, M. Živná, S. Kmoch, N. K. Fennelly, P. O’Kelly, K. A. Benson, E. T. Conlon, G. Cavalleri, C. Foley, B. Doyle, A. Dorman, M. A. Little, P. Lavin, K. Kidd, A. J. Bleyer, P. J. Conlon
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of progressive chronic kidney disease (CKD) and end-stage renal disease (ESRD) [1]. Causative mutations have been identified in the MUC1 gene encoding mucin-1, the UMOD gene encoding uromodulin (previously Tamm-Horsfall protein), the REN gene encoding renin, the HNF1B gene encoding hepatocyte nuclear factor 1beta, and the SEC61A1 gene encoding translocon subunit SEC61A [1–4]. The cardinal features include gradual loss of kidney function, histological evidence of tubular atrophy and interstitial fibrosis and an autosomal dominant inheritance pattern. Urinary sediment is typically bland. The mean age of ESRD is approximately 45 years but this is variable [5,6]. KDIGO consensus guidelines recommend criteria for diagnosis of confirmed or suspected ADTKD [7].
Related Knowledge Centers
- Eukaryote
- Lipid Bilayer
- Membrane Protein
- Peptide
- Prokaryote
- Protein
- Pathogen
- Endoplasmic Reticulum
- Cytosol
- Sec61