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Idiotypes and T Cell Selection
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Bjarne Bogen, Zlatko Dembić, Siegfried Weiss
In addition to the conventional class II pathway utilized for processing of extracellularly derived Ig and presentation of Id, newly synthesized λ2315 Ig in B lymphoma cells probably is processed in the endoplasmic reticulum (ER) or a pre-Golgi apparatus ratus compartment [21,42]. The KDEL motif attached to λ2315 was thought to cause retention of proteins prior to cis-Golgi. However, it is now known that KDEL-tagged proteins, although usually found in the ER, may travel until trans-Golgi before being retrieved [43]. Since signals involved in cellular traffic are often leaky, transport of minor amounts of λ2315 into an endocytic compartment cannot be excluded so far. In this endogenous pathway for Id presentation, neither display on the cell surface nor secretion of λ2315 Ig is required [42]. Others have also demonstrated processing of endogenous antigen in or close to the ER [44,45] and an ER proteolytic degradation pathway has been described [46,47]. Furthermore, binding of synthetic peptides to nascent class II molecules has been demonstrated in vitro in microsomes, even in the presence of invariant chain, which is supposed to block the binding site of MHC class II in the ER [48,49]. Moreover, peptides derived from proteins in the secretory pathway, and in particular Ig peptides, are frequently eluted from class II molecules [35–37] (however, such elution studies do not identify where in the cell the processing occurs).
Alteration in Cell Cycle Control Factors and the Induction of Oxygen-Regulated Proteins by Hypoxic Stress
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Harold C. Smith, Robert L. Howell, John W. Ludlow
The function of GRP/ORP in normal cell physiology and ischemic stress response remains to be conclusively demonstrated. Microsequence analysis has revealed that GRP 78 and ORP 80 are identical to BiP,13,20,21 an endoplasmic reticulum protein containing a C-terminal KDEL sequence involved in the retention of malfolded proteins in the endoplasmic reticulum following stress.22,24 It is interesting to note that these proteins belong to the heat shock protein superfamily.20,25,26 However, the classic heat shock proteins (described in Reference 26 and other chapters within this volume) are induced by ischemia only following prolonged periods of hypoxia and subsequent to GRP/ORP induction (within 12 to 24 h of the induction of hypoxia).7,10,13 It might be concluded therefore that while GRP/ORP are in a category of essential stress-induced proteins, their role may be distinct from heat shock proteins in either their function or intracellular site of action. As with the GRP/ORP adaptive response described above, repeated short-term hypoxic episodes will shorten the lag period for heat shock protein induction in response to subsequent hypoxic stress.
Post-Translational Regulation of C-Reactive Protein Secretion
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Stephen S. Macintyre, Patricia A. Kalonick
Proteins which are cotranslationally inserted into the lumen of the ER during their synthesis have varied destinations, including the plasma membrane, the extracellular space, lysosomes, elements of the Golgi apparatus, and the ER itself. Thus, the need for specific delivery of a diversity of proteins to multiple locations represents a formidable task in protein trafficking. The mechanism by which newly synthesized lysosomal enzymes are specifically targeted to lysosomes has been well characterized.1 Considerable progress has also been made in eluciding the role of the carboxyl terminal KDEL,2 or homologous,3-5 sequence in the continuous retrieval of soluble ER resident proteins from downstream compartments to their proper location within the lumen of the ER.2,6,7 More recently, several reports have begun to identify sequence and/or structural motifs of certain transmembrane proteins which allow for their specific localization to the membranes of the ER and Golgi elements.8-12
Surface-exposed and soluble calreticulin: conflicting biomarkers for cancer prognosis
Published in OncoImmunology, 2020
Oliver Kepp, Peng Liu, Liwei Zhao, Isabelle Plo, Guido Kroemer
Exon 9 mutations of CALR have been identified in up to 30% of patients affected by myeloproliferative neoplasms (MPNs) such as essential thrombocythemia (ET) and myelofibrosis (MF).33,34 The most recurrent mutations typically manifest as either a 52 base pair deletion of residues 1092 to 1142 (CALRdel52) or a 5 base pair insertion between residues 1154 and 1155 (CALRins5). Both mutations lead to an alternative open reading frame, resulting in similar changes in the C-terminal amino acid sequence of the protein that becomes positively charged and loses the KDEL ER retention signal.35 Consequently, mutant CALR protein fails to be detected by KDEL retention receptors and thus enters the conventional protein secretion pathway and is released via Golgi-mediated exocytosis.30,36,37 Secreted CALR mutants bind (via their lectin binding sites) to the extracellular domain of the thrombopoietin receptor (MPL) in a cell autonomously or paracrine fashion thus leading to a downstream activation of the Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT) proteins STAT1, STAT3 and STAT5.38-41 Introduction of analogous CALR mutations into mice recapitulates the ET-like disease and its progression to myelofibrosis.41-43 Thus, CALR mutants act as oncogenic driver of MPN.39,41,44,45 Moreover, patients with MPN-associated CALR mutations exhibit an increase in myeloid derived suppressor cells (MDSC) and immunosuppressive B cells, suggesting that mutated CALR may subvert immune responses.44,46
Moxetumomab pasudotox for the treatment of relapsed and/or refractory hairy cell leukemia
Published in Expert Review of Hematology, 2019
Iman Abou Dalle, Farhad Ravandi
The new recombinant murine immunotoxin is now composed of two variable heavy (VH) and light (VL) chains, linked by disulfide bond. The carboxy terminus of VH is connected to a truncated form of pseudomonas exotoxin (PE38). The toxin PE38 is a 38 kDa fragment of pseudomonas exotoxin A, deprived from its binding domain and only contains domain 2 (amino acids 253–364), 1a (amino acids 381–399), and the catalytic domain 3 (amino acids 400–613). The immunotoxin binds to CD22 antigen expressed on the surface of HCL cells; it then internalizes by endocytosis. The toxin traffics to the endoplasmic reticulum using the KDEL receptor (endoplasmic reticulum protein retention receptor-1). Once in the cytosol, the enzymatic part of domain 3 induces adenosine diphosphate (ADP) ribosylation of the diphthamide residue in elongation factor-2 (EF-2) leading finally to protein synthesis inhibition including anti-apoptotic protein MCL-1 and therefore cell death apoptosis [28,30,37]. (Figure 1)
Intracellular sequestration of HER2 via targeted subcellular peptide delivery
Published in Journal of Drug Targeting, 2018
Zachary F. Walls, Matthew Schwengels, Victoria Palau
The AMIDST was composed of a cell-penetrating domain and multiple modular peptide domains. To confer membrane translocation, the transduction domain of the trans-activating transcriptional activator (TAT) from human immunodeficiency virus (HIV-1) was used [13]. TAT was chosen for its capacity to carry many different types of cargo across the plasma membrane [14]. A Furin cleavage site was inserted between the TAT and modular domains to remove the plasma membrane transduction domain and expose the organelle-targeting sequence following internalisation [15]. This site was chosen due to its absence in the remainder of the AMIDST sequence as well as Furin’s ubiquitous expression and cytoplasmic localisation [16]. To confer targeting to secretory organelles, the immunoglobulin kappa light chain (Igκ) leader sequence was used. This sequence was chosen based on its commercial use for efficient secretion of recombinant proteins in mammalian cells [14]. To confer HER2-targeting, the EGF-I domain of ASGP2 (ascites sialoglycoprotein-2) was fused downstream of the Igκ leader sequence [17]. This peptide has been shown to reliably interact with HER2 in multiple contexts [10,18]. The influenza hemagluttinin tag (HA-tag) was fused downstream of the EGF domain to facilitate staining in later experiments. Finally, the KDEL sequence was fused to the C-terminus of AMIDST to anchor the complex within the membranes of secretory organelles [19].