scholarly journals The pivotal role of ERp44 in patrolling protein secretion

2020 ◽  
Vol 133 (21) ◽  
pp. jcs240366
Author(s):  
Tiziana Tempio ◽  
Tiziana Anelli
Keyword(s):  
Quality Control ◽  
Membrane Trafficking ◽  
Cell Biology ◽  
Secretory Pathway ◽  
Oligomeric Proteins ◽  
Protein Ligands ◽  
Intermediate Compartment ◽  
Definition Of ◽  
Main Language

ABSTRACTInteractions between protein ligands and receptors are the main language of intercellular communication; hence, how cells select proteins to be secreted or presented on the plasma membrane is a central concern in cell biology. A series of checkpoints are located along the secretory pathway, which ensure the fidelity of such protein signals (quality control). Proteins that pass the checkpoints operated in the endoplasmic reticulum (ER) by the binding immunoglobulin protein (BiP; also known as HSPA5 and GRP78) and the calnexin–calreticulin systems, must still overcome additional scrutiny in the ER-Golgi intermediate compartment (ERGIC) and the Golgi. One of the main players of this process in all metazoans is the ER-resident protein 44 (ERp44); by cycling between the ER and the Golgi, ERp44 controls the localization of key enzymes designed to act in the ER but that are devoid of suitable localization motifs. ERp44 also patrols the secretion of correctly assembled disulfide-linked oligomeric proteins. Here, we discuss the mechanisms driving ERp44 substrate recognition, with important consequences on the definition of ‘thiol-mediated quality control’. We also describe how pH and zinc gradients regulate the functional cycle of ERp44, coupling quality control and membrane trafficking along the early secretory compartment.

ERGIC-53 and traffic in the secretory pathway

2000 ◽  
Vol 113 (4) ◽  
pp. 587-596 ◽  
Author(s):  
H.P. Hauri ◽  
F. Kappeler ◽  
H. Andersson ◽  
C. Appenzeller
Keyword(s):  
Cystic Fibrosis ◽  
Protein Trafficking ◽  
Cell Biology ◽  
Secretory Pathway ◽  
Viral Infections ◽  
Cultured Cells ◽  
Intermediate Compartment ◽  
Retrograde Traffic ◽  
Specific Membrane ◽  
Transport Receptor

The ER-Golgi intermediate compartment (ERGIC) marker ERGIC-53 is a mannose-specific membrane lectin operating as a cargo receptor for the transport of glycoproteins from the ER to the ERGIC. Lack of functional ERGIC-53 leads to a selective defect in secretion of glycoproteins in cultured cells and to hemophilia in humans. Beyond its interest as a transport receptor, ERGIC-53 is an attractive probe for studying numerous aspects of protein trafficking in the secretory pathway, including traffic routes, mechanisms of anterograde and retrograde traffic, retention of proteins in the ER, and the function of the ERGIC. Understanding these fundamental processes of cell biology will be crucial for the elucidation and treatment of many inherited and acquired diseases, such as cystic fibrosis, Alzheimer's disease and viral infections.

scholarly journals Bring it back, bring it back, don't take it away from me – the sorting receptor RER1

2020 ◽  
Vol 133 (17) ◽  
pp. jcs231423
Author(s):  
Wim Annaert ◽  
Christoph Kaether
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Future Directions ◽  
Binding Motifs ◽  
Sorting Receptor ◽  
Intermediate Compartment ◽  
The Brain

ABSTRACTThe quote “bring it back, bring it back, don't take it away from me” from Queen's Love of my life describes the function of the sorting receptor RER1, a 23 kDa protein with four transmembrane domains (TMDs) that localizes to the intermediate compartment and the cis-Golgi. From there it returns escaped proteins that are not supposed to leave the endoplasmic reticulum (ER) back to it. Unique about RER1 is its ability to recognize its ligands through binding motifs in TMDs. Among its substrates are ER-resident proteins, as well as unassembled subunits of multimeric complexes that are retrieved back into the ER, this way guarding the full assembly of their respective complexes. The basic mechanisms for RER1-dependent retrieval have been already elucidated some years ago in yeast. More recently, several important cargoes of RER1 have been described in mammalian cells, and the in vivo role of RER1 is being unveiled by using mouse models. In this Review, we give an overview of the cell biology of RER1 in different models, discuss its controversial role in the brain and provide an outlook on future directions for RER1 research.

scholarly journals An endoplasmic reticulum storage disease causing congenital goiter with hypothyroidism.

1996 ◽  
Vol 133 (3) ◽  
pp. 517-527 ◽  
Author(s):  
P S Kim ◽  
O Y Kwon ◽  
P Arvan
Keyword(s):  
Quality Control ◽  
Cell Biology ◽  
Intracellular Transport ◽  
Secretory Pathway ◽  
Storage Disease ◽  
Thyroid Tissue ◽  
Temperature Sensitive ◽  
Control Mechanisms ◽  
Er Quality Control ◽  
Hormone Synthesis

In humans, deficient thyroglobulin (Tg, the thyroid prohormone) is an important cause of congenital hypothyroid goiter; further, homozygous mice expressing two cog/cog alleles (linked to the Tg locus) exhibit the same phenotype. Tg mutations might affect multiple different steps in thyroid hormone synthesis; however, the microscopic and biochemical phenotype tends to involve enlargement of the thyroid ER and accumulation of protein bands of M(r) < 100. To explore further the cell biology of this autosomal recessive illness, we have examined the folding and intracellular transport of newly synthesized Tg in cog/cog thyroid tissue. We find that mutant mice synthesize a full-length Tg, which appears to undergo normal N-linked glycosylation and glucose trimming. Nevertheless, in the mutant, Tg is deficient in the folding that leads to homodimerization, and there is a deficiency in the quantity of intracellular Tg transported to the distal portion of the secretory pathway. Indeed, we find that the underlying disorder in cog/cog mice is a thyroid ER storage disease, in which a temperature-sensitive Tg folding defect, in conjunction with normal ER quality control mechanisms, leads to defective Tg export. In relation to quality control, we find that the physiological response in this illness includes the specific induction of five molecular chaperones in the thyroid ER. Based on the pattern of chaperone binding, different potential roles for individual chaperones are suggested in glycoprotein folding, retention, and degradation in this ER storage disease.

scholarly journals Conserved function of ether lipids and sphingolipids in the early secretory pathway

2019 ◽  
Author(s):  
Noemi Jiménez-Rojo ◽  
Manuel D. Leonetti ◽  
Valeria Zoni ◽  
Adai Colom ◽  
Suihan Feng ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Cell Biology ◽  
Secretory Pathway ◽  
Protein Transport ◽  
Lipid Synthesis ◽  
Chemical Properties ◽  
Ether Lipid ◽  
Ether Lipids ◽  
Early Secretory Pathway ◽  
A Genome

ABSTRACTSphingolipids have been shown to play important roles in physiology and cell biology, but a systematic examination of their functions is lacking. We performed a genome-wide CRISPRi screen in sphingolipid-depleted cells and identified hypersensitive mutants in genes of membrane trafficking and lipid biosynthesis, including ether lipid synthesis. Systematic lipidomic analysis showed a coordinate regulation of ether lipids with sphingolipids, where depletion of one of these lipid types resulted in increases in the other, suggesting an adaptation and functional compensation. Biophysical experiments on model membranes show common properties of these structurally diverse lipids that also share a known function as GPI anchors in different kingdoms of life. Molecular dynamics simulations show a selective enrichment of ether phosphatidylcholine around p24 proteins, which are receptors for the export of GPI-anchored proteins and have been shown to bind a specific sphingomyelin species. Our results support a model of convergent evolution of proteins and lipids, based on their physico-chemical properties, to regulate GPI-anchored protein transport and maintain homeostasis in the early secretory pathway.

scholarly journals Role of N-oligosaccharide endoplasmic reticulum processing reactions in glycoprotein folding and degradation

2000 ◽  
Vol 348 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Armando J. PARODI
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Secretory Pathway ◽  
Cell Recognition ◽  
Glucosidase Ii ◽  
Membrane Bound ◽  
Quaternary Structures ◽  
Lectin Recognition

The endoplasmic reticulum (ER) is the subcellular site where proteins following the secretory pathway acquire their proper tertiary and, in certain cases, quaternary structures. Species that are not yet properly folded are prevented from exit to the Golgi apparatus and, if permanently misfolded, are transported to the cytosol, where they are degraded in the proteasomes. This review deals with a mechanism, applicable to proteins that are N-glycosylated in the ER, by which the quality control of folding is performed. Protein-linked monoglucosylated glycans, formed by glucosidase I- and glucosidase II-dependent partial deglucosylation of the oligosaccharides transferred from dolichol diphosphate derivatives in N-glycosylation (Glc3Man9GlcNAc2), mediate glycoprotein recognition by two ER-resident lectins, membrane-bound calnexin (CNX) and its soluble homologue, calreticulin (CRT). A still not yet fully confirmed interaction between the lectins and the protein moieties of folding glycoproteins may occur after lectin recognition of monoglucosylated structures. Further deglucosylation of glycans by glucosidase II, and perhaps also by a change in CNX/CRT and/or in the substrate glycoprotein conformation, liberates the glycoproteins from their CNX/CRT anchors. Glycans may be then reglucosylated by the UDP-Glc:glycoprotein glucosyltransferase (GT), and thus be recognized again by CNX/CRT, but only when linked to not yet properly folded protein moieties, as this enzyme behaves as a sensor of glycoprotein conformation. Deglucosylation/reglucosylation cycles catalysed by the opposing activities of glucosidase II and GT only stop when proper folding is achieved. The interaction between CNX/CRT and a monoglucosylated glycan is one of the alternative mechanisms by which cells retain not yet properly folded glycoproteins in the ER; in addition, it enhances folding efficiency by preventing protein aggregation and thus allowing intervention of classical chaperones and other folding-assisting proteins. There is evidence suggesting that both glycoprotein glucosylation and mannose removal, respectively mediated by GT and ER mannosidase I, might be involved in cell recognition of permanently misfolded glycoproteins bound for proteasome degradation.

scholarly journals Endoplasmic reticulum acetyltransferases Atase1 and Atase2 differentially regulate reticulophagy, macroautophagy and cellular acetyl-CoA metabolism

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael J. Rigby ◽  
Alexis J. Lawton ◽  
Gulpreet Kaur ◽  
Varuna C. Banduseela ◽  
William E. Kamm ◽  
...  
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Control Mechanism ◽  
Cellular Biology ◽  
Lysine Acetylation ◽  
Type Ii ◽  
Acetyl Coa ◽  
Toxic Protein ◽  
Quality Control Mechanism

AbstractNε-lysine acetylation in the ER lumen is a recently discovered quality control mechanism that ensures proteostasis within the secretory pathway. The acetyltransferase reaction is carried out by two type-II membrane proteins, ATase1/NAT8B and ATase2/NAT8. Prior studies have shown that reducing ER acetylation can induce reticulophagy, increase ER turnover, and alleviate proteotoxic states. Here, we report the generation of Atase1−/− and Atase2−/− mice and show that these two ER-based acetyltransferases play different roles in the regulation of reticulophagy and macroautophagy. Importantly, knockout of Atase1 alone results in activation of reticulophagy and rescue of the proteotoxic state associated with Alzheimer’s disease. Furthermore, loss of Atase1 or Atase2 results in widespread adaptive changes in the cell acetylome and acetyl-CoA metabolism. Overall, our study supports a divergent role of Atase1 and Atase2 in cellular biology, emphasizing ATase1 as a valid translational target for diseases characterized by toxic protein aggregation in the secretory pathway.

Challenges of Fear Conditioning Research in the Age of RDoC

2017 ◽  
Vol 225 (3) ◽  
pp. 189-199 ◽  
Author(s):  
Tina B. Lonsdorf ◽  
Jan Richter
Keyword(s):  
Fear Conditioning ◽  
Clinical Diagnosis ◽  
Research Domain Criteria ◽  
Major Focus ◽  
The Future ◽  
Definition Of ◽  
Methodological Considerations ◽  
Research Domain

Abstract. As the criticism of the definition of the phenotype (i.e., clinical diagnosis) represents the major focus of the Research Domain Criteria (RDoC) initiative, it is somewhat surprising that discussions have not yet focused more on specific conceptual and procedural considerations of the suggested RDoC constructs, sub-constructs, and associated paradigms. We argue that we need more precise thinking as well as a conceptual and methodological discussion of RDoC domains and constructs, their interrelationships as well as their experimental operationalization and nomenclature. The present work is intended to start such a debate using fear conditioning as an example. Thereby, we aim to provide thought-provoking impulses on the role of fear conditioning in the age of RDoC as well as conceptual and methodological considerations and suggestions to guide RDoC-based fear conditioning research in the future.

Sign in / Sign up

Export Citation Format

Share Document