Post-Translational Regulation of C-Reactive Protein Secretion
Andrzej Mackiewicz, Irving Kushner, Heinz Baumann in Acute Phase Proteins, 2020
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
Molecular Farming Antibodies in Plants: From Antibody Engineering to Antibody Production
Maurizio Zanetti, J. Donald Capra in The Antibodies, 2002
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].
Golgi apparatus regulation of differentiation
C. Yan Cheng in Spermatogenesis, 2018
The testis-specific PDILT performs a specialized chaperone function by liaising with partner proteins in disulfide-dependent complexes within germ cells of the testis.113 The PDI family member erp44 (endoplasmic reticulum resident protein) is now accepted to be Golgi localized in most cell types but whose localization changes to ER depending on its cargo.114,115 A known PDILT client in germ cells is the acrosome located membrane protein ADAM3 (a disintegrin and metalloprotease).113,116 However, after localizing to the Golgi and acrosome from steps 1–7 (solid brown line, Figure 1.13a), PDILT relocalizes to the cytoplasm (ER) where it is present from steps 8–19 (stippled brown line, Figure 1.13c).113,117 Hence, it is the PDILT client proteins that likely dictate its localization to specific organelles of the secretory pathway.
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.
BTN3A is a prognosis marker and a promising target for Vγ9Vδ2 T cells based-immunotherapy in pancreatic ductal adenocarcinoma (PDAC)
Published in OncoImmunology, 2018
Audrey Benyamine, Céline Loncle, Etienne Foucher, Juan-Luis Blazquez, Céline Castanier, Anne-Sophie Chrétien, Mauro Modesti, Véronique Secq, Salem Chouaib, Meritxell Gironella, Elena Vila-Navarro, Giuseppe Montalto, Jean-Charles Dagorn, Nelson Dusetti, Juan Iovanna, Daniel Olive
Here, the expression of BTN3A1 and BTN3A2 was higher under stress condition, whereas BTN3A surface expression remained stable. This indicates a tight regulation of membrane BTN3A expression that might occur through the intracellular retention of BTN3A1 and BTN3A2 in the endoplasmic reticulum due to the presence of canonical ER retention/retrieval signals in their intracellular domains (Vantouroux et al., γδ T cell conference 2016) or via BTN3A isoforms shedding. Accordingly, we observed soluble BTN3A isoforms including soluble BTN3A1 in the supernatants of pancreatic cell lines and in the plasma of PDAC patients. In addition, we showed that BTN3A shedding occurred in manner that is in part MMP-dependent, similar to that previously described for the NKG2D ligands MICA/B. We can assume that this increased release might result from enhanced MMP activity and BTN3A expression in PDAC patients. Indeed, both levels of soluble BTN3A and of BTN3A surface expression were associated with a poor prognosis of PDAC patients. Conversely, in patient with inflammatory or non-malignant pancreatic aggression such as chronic calcificating pancreatitis and intraductal papillary mucinous neoplasm, soluble BTN3A1 levels were not different from those found in healthy donors. This suggests that BTN3A1 upregulation might be a specific feature of PDAC associated inflammation.
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].
Related Knowledge Centers
- Golgi Apparatus
- Protein
- Protein Folding
- Signal Peptide
- Amino Acid
- Endoplasmic Reticulum
- N-Terminus
- C-Terminus
- Kdel
- Kkxx