scholarly journals Protein folding state-dependent sorting at the Golgi apparatus

2019 ◽  
Vol 30 (17) ◽  
pp. 2296-2308 ◽  
Author(s):  
Doris Hellerschmied ◽  
Yevgeniy V. Serebrenik ◽  
Lin Shao ◽  
George M. Burslem ◽  
Craig M. Crews
Keyword(s):  
Quality Control ◽  
Golgi Apparatus ◽  
Protein Unfolding ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Specific Protein ◽  
Major Protein ◽  
Unfolded Proteins ◽  
Lysosomal Degradation ◽  
Folded Proteins

In eukaryotic cells, organelle-specific protein quality control (PQC) is critical for maintaining cellular homeostasis. Despite the Golgi apparatus being the major protein processing and sorting site within the secretory pathway, how it contributes to PQC has remained largely unknown. Using different chemical biology-based protein unfolding systems, we reveal the segregation of unfolded proteins from folded proteins in the Golgi. Quality control (QC) substrates are subsequently exported in distinct carriers, which likely contain unfolded proteins as well as highly oligomerized cargo that mimic protein aggregates. At an additional sorting step, oligomerized proteins are committed to lysosomal degradation, while unfolded proteins localize to the endoplasmic reticulum (ER) and associate with chaperones. These results highlight the existence of checkpoints at which QC substrates are selected for Golgi export and lysosomal degradation. Our data also suggest that the steady-state ER localization of misfolded proteins, observed for several disease-causing mutants, may have different origins.

scholarly journals Activation of Mammalian Unfolded Protein Response Is Compatible with the Quality Control System Operating in the Endoplasmic Reticulum

2004 ◽  
Vol 15 (6) ◽  
pp. 2537-2548 ◽  
Author(s):  
Satomi Nadanaka ◽  
Hiderou Yoshida ◽  
Fumi Kano ◽  
Masayuki Murata ◽  
Kazutoshi Mori
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control System ◽  
Golgi Apparatus ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Protein Response

Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.

scholarly journals Control of Protein Homeostasis in the Early Secretory Pathway: Current Status and Challenges

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1347 ◽  
Author(s):  
Sicari ◽  
Igbaria ◽  
Chevet
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Secretory Protein ◽  
Human Diseases ◽  
Current Status ◽  
Cellular Functions ◽  
Early Secretory Pathway ◽  
Folded Proteins ◽  
Therapeutic Tools

: Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors involved in such process, both endoplasmic reticulum (ER) and the Golgi complex play prominent roles in protein synthesis, biogenesis and secretion. ER and Golgi functions ensure that only properly folded proteins are allowed to flow through the secretory pathway while improperly folded proteins have to be eliminated to not impinge on cellular functions. Thus, complex quality control and degradation machineries are crucial to prevent the toxic accumulation of improperly folded proteins. However, in some instances, improperly folded proteins can escape the quality control systems thereby contributing to several human diseases. Herein, we summarize how the early secretory pathways copes with the accumulation of improperly folded proteins, and how insufficient handling can cause the development of several human diseases. Finally, we detail the genetic and pharmacologic approaches that could be used as potential therapeutic tools to treat these diseases.

scholarly journals Translational Regulation of Pmt1 and Pmt2 by Bfr1 Affects Unfolded Protein O-Mannosylation

2019 ◽  
Vol 20 (24) ◽  
pp. 6220 ◽  
Author(s):  
Joan Castells-Ballester ◽  
Natalie Rinis ◽  
Ilgin Kotan ◽  
Lihi Gal ◽  
Daniela Bausewein ◽  
...  
Keyword(s):  
Quality Control ◽  
Translational Regulation ◽  
Secretory Pathway ◽  
Rna Binding ◽  
Protein Quality ◽  
Fluorescent Protein ◽  
Brefeldin A ◽  
Protein Quality Control ◽  
Ribosome Profiling ◽  
Unfolded Protein

O-mannosylation is implicated in protein quality control in Saccharomyces cerevisiae due to the attachment of mannose to serine and threonine residues of un- or misfolded proteins in the endoplasmic reticulum (ER). This process also designated as unfolded protein O-mannosylation (UPOM) that ends futile folding cycles and saves cellular resources is mainly mediated by protein O-mannosyltransferases Pmt1 and Pmt2. Here we describe a genetic screen for factors that influence O-mannosylation in yeast, using slow-folding green fluorescent protein (GFP) as a reporter. Our screening identifies the RNA binding protein brefeldin A resistance factor 1 (Bfr1) that has not been linked to O-mannosylation and ER protein quality control before. We find that Bfr1 affects O-mannosylation through changes in Pmt1 and Pmt2 protein abundance but has no effect on PMT1 and PMT2 transcript levels, mRNA localization to the ER membrane or protein stability. Ribosome profiling reveals that Bfr1 is a crucial factor for Pmt1 and Pmt2 translation thereby affecting unfolded protein O-mannosylation. Our results uncover a new level of regulation of protein quality control in the secretory pathway.

scholarly journals Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress

2019 ◽  
Vol 116 (23) ◽  
pp. 11291-11298 ◽  
Author(s):  
Aeid Igbaria ◽  
Philip I. Merksamer ◽  
Ala Trusina ◽  
Firehiwot Tilahun ◽  
Jeffrey R. Johnson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Fluorescent Protein ◽  
Control Process ◽  
Secretory Proteins ◽  
Quality Control Process ◽  
Folded Proteins ◽  
Green Fluorescent

Diverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such “ER stress,” we employed an ER-targeted, redox-responsive, green fluorescent protein—eroGFP—that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress regimes cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to “reflux” back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in Saccharomyces cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and cochaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.

scholarly journals Protein quality control in the early secretory pathway

2008 ◽  
Vol 27 (2) ◽  
pp. 315-327 ◽  
Author(s):  
Tiziana Anelli ◽  
Roberto Sitia
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Early Secretory Pathway

scholarly journals ER-Associated Degradation of Membrane Proteins in Yeast

2006 ◽  
Vol 6 ◽  
pp. 967-983 ◽  
Author(s):  
Cédric Pety de Thozée ◽  
Michel Ghislain
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Control Systems ◽  
Protein Unfolding ◽  
Secretory Pathway ◽  
Retrograde Transport ◽  
26S Proteasome ◽  
Post Translational Modifications ◽  
Final Destination ◽  
Polypeptide Folding

Proteins destined for the secretory pathway are translocated into the endoplasmic reticulum (ER), where they are subjected to a variety of post-translational modifications before they reach their final destination. Newly synthesized proteins that have defect in polypeptide folding or subunit assembly are recognized by quality control systems and eliminated by the 26S proteasome, a cytosolic ATP-dependent proteolytic machinery. Delivery of non-native ER proteins to the proteasome requires retrograde transport across the ER membrane and depends on a protein-unfolding machine consisting of Cdc48p, Ufd1p, and Npl4p. Recent studies in yeast have highlighted the possible function of the Sar1p/COPII machinery in ER-associated degradation of some lumenal and membrane proteins.

scholarly journals Possible involvement of endoplasmic reticulum stress in the pathogenesis of Alzheimer’s disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
Yasuyuki Nomura
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Quality ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.

Calnexin: a molecular chaperone with a taste for carbohydrate

1995 ◽  
Vol 73 (3-4) ◽  
pp. 123-132 ◽  
Author(s):  
David B. Williams
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Secretory Pathway ◽  
Quaternary Structure ◽  
Integral Membrane Protein ◽  
Secretory Proteins ◽  
Chaperone Function ◽  
Folded Proteins

Calnexin is an integral membrane protein of the endoplasmic reticulum (ER) that binds transiently to a wide array of newly synthesized membrane and secretory proteins. It also exhibits prolonged binding to misfolded or incompletely folded proteins. Recent studies have demonstrated that calnexin functions as a molecular chaperone to facilitate the folding and assembly of proteins in the ER. It is also a component of the quality control system that prevents proteins from progressing along the secretory pathway until they have acquired proper tertiary or quaternary structure. Most proteins that are translocated into the ER are glycosylated at Asn residues, and calnexin's interactions are almost exclusively restricted to proteins that possess this posttranslational modification. The preference for glycoproteins resides in calnexin's ability to function as a lectin with specificity for the GlC1Man9GlcNAc2 oligosaccharide, an early intermediate in the processing of Asn-linked oligosaccharides. Calnexin also has the capacity to bind to polypeptide segments of unfolded glycoproteins. Available evidence suggests that calnexin utilizes its lectin property during initial capture of a newly synthesized glycoprotein and that subsequent association (and chaperone function) is mediated through polypeptide interactions. Unlike other molecular chaperones that are soluble proteins, calnexin is an intrinsic component of the ER membrane. Its unique ability to capture unfolded glycoproteins through their large oligosaccharide moieties may have evolved as a means to overcome accessibility problems imposed by being constrained within a lipid bilayer.Key words: protein folding, molecular chaperones, calnexin, quality control, endoplasmic reticulum.

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