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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
While much evidence indicates that the process of quality control within the ER can prevent secretion or accumulation of abnormal proteins, the extent to which ER retention may also serve to post-translationally regulate the intracellular trafficking of normally assembled integral membrane and secretory proteins is not clear. For example, although it is widely recognized that different secretory proteins exit the ER at varying rates,23,27 the mechanisms underlying this observation are not understood. A currently prevailing hypothesis suggests that in the absence of specific targeting signals, secretory proteins are transported to the cell surface by a default pathway of rapid bulk flow of vesicular contents.28 However, there is also evidence that “positive” sorting signals may be required to facilitate the exit of α1-antitrypsin and proalbumin from the ER.29-31
Role of Steroids in the Onset of Labor
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Guy Germain, Leroy Marie Josèphe, Michelle Breuiller-Fouche
The binding of progesterone and estrogen receptors to their cognate response elements (ERE and PRE) is at the basis of the regulation of transcription of hormone-sensitive genes.7 Many studies have established in the primate and rodent uterus that nuclear ER retention parallels rising plasma estrogen levels during the proliferative phase of the cycle, and that nuclear ER declines during the postovulatory period as plasma progesterone rises.79,80 This led to the general statement that ER reduction reflects the way progesterone removes the influence of estrogen from the cell and thereby antagonizes estrogen-driven events. Uterine PR are known to be under dual control. Estrogens stimulate the synthesis of PR and progesterone induces the loss of its own receptor. Along this line, the down-regulation of PR by progesterone seems to be incompatible with the inhibition or modulation of estrogen action during pregnancy, because high circulating plasma progesterone is chronically maintained in the presence of estrogens. One explanation for this paradox might be that progesterone could desensitize the uterus to progesterone action by permitting a recovery of nuclear ER.
Molecular Farming Antibodies in Plants: From Antibody Engineering to Antibody Production
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 2002
Rainer Fischer, Ricarda Finnern, Olga Artsaenko, Stefan Schillberg
Plants can be optimized as antibody bioreactors by exploiting the innate protein sorting and targeting mechanisms plant cells use to target endogenous proteins to organelles. Recombinant antibodies have been successfully expressed in the following plant cell sub-compartments: the intercellular space beneath the cell wall (apoplast), chloroplasts and endoplasmic reticulum (ER) [2, 202, 238, 241, 252-254, 257, 261]. Expression of rAbs in the cytoplasm has only been achieved using scFv fragments [239, 240, 260, 261]. Retaining expressed proteins within the ER currently gives the highest yield of functional protein but targeting them for secretion to the apoplast leads to significant levels of functional antibody expression. ER retention can give 10- to 100-fold increases in target protein yield compared to secretion [202]. This may be because of the presence of the molecular chaperones in the ER that promote efficient, accurate protein folding. Furthermore, rAb expression can be optimized by the use of stronger constitutive promoters in the expression vectors, tissue-specific or inducible promoters, improvement of transcript stability, translational enhancement with viral sequences and optimization of codon usage to meet the plant pattern [270].
Orally delivered rutin in lipid-based nano-formulation exerts strong antithrombotic effects by protein disulfide isomerase inhibition
Published in Drug Delivery, 2022
Dan Chen, Yurong Liu, Peiwen Liu, Yang Zhou, Longguang Jiang, Cai Yuan, Mingdong Huang
Recently, a surging number of researches have revealed that PDI plays a prominent role in the initial stage of thrombosis. In general, PDI contains endoplasmic reticulum (ER) retention signals and is found in high concentrations in the ER; however, PDI can also escape ER retention mechanism and localize to secretory granules and membrane surface in platelets and endothelial cells once vascular injury or inflammation occurs (Turano et al., 2002). However, a strong direct link between PDI and coagulation cascade or coagulation regulatory pathways has not been consensually established. What is encouraging is that some PDI inhibitors, e.g. quercetin and its derivatives, such as rutin, were found to have strong anticoagulatory effects without bleeding side effects (Jasuja et al., 2012). We showed that rutin binds directly to b’x domain of PDI, inducing a more compact conformation of PDI with less flexibility (Lin et al., 2015a). In clinical practice, troxerutin, a trihydroxyethylated derivative of rutin, has been proved to strengthen the wall of blood vessels, and is used as a vasoprotective (Wang et al., 2017).
Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma
Published in Expert Review of Hematology, 2020
Slavisa Ninkovic, Simon J. Harrison, Hang Quach
The N-terminal domain of GRP78 targets the protein to the ER, while the C-terminal KDEL motif marks it for retention in the ER, where the ATPase and substrate binding domains facilitate protein folding [20,21]. GRP78 does not have a classical hydrophobic transmembrane region that would anchor it to the cell surface, instead, the presence on the cell surface appears to be dependent on interactions with other cell-surface proteins [22,23]. The exact mechanisms of translocation from the ER to the cell surface remain unclear but over-saturation of the ER retention system, especially at times of ER stress and increased GRP78 expression and co-translocation with cell-surface proteins following their interaction with GRP78 in the ER, have been suggested to facilitate GRP78 translocation [22,24,25].
Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders
Published in Expert Review of Clinical Pharmacology, 2018
Zhi-Shuai Hou, Alfredo Ulloa-Aguirre, Ya-Xiong Tao
Proteins are required to pass the inspection of the stringent ER QCS in order to be incorporated into transport vesicles for delivery to the Golgi and thereafter to their site of function [8,30]. Nevertheless, some misfolded proteins bearing particular ER retention signals or when ERAD is saturated can escape the ER QCS and translocate to the Golgi [49], whereas others may misfold during trafficking. This relative inefficiency of the ER QCS is compensated by Golgi checkpoints [8,50,51], which upon recognition of non-native, misfolded membrane protein domains, promote either their ER retrieval via retrotranslocation through the ER-Golgi intermediate compartment (ERGIC) and ERAD or their retention in the Golgi for delivering to lysosomes [23,52]. Quality control at the Golgi apparatus also regulates proteostasis by sorting already mature proteins to their final destination or by processing the proteins imported from the ER before sorting to their site of function [53,54]. Quality control at the ER and Golgi are thus required for maintenance of proteostasis and adequate cell function.