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 A Striking Quality Control Subcompartment in Saccharomyces cerevisiae: The Endoplasmic Reticulum-associated Compartment

2004 ◽  
Vol 15 (2) ◽  
pp. 908-921 ◽  
Author(s):  
Gregory Huyer ◽  
Gaby L. Longsworth ◽  
Deborah L. Mason ◽  
Monica P. Mallampalli ◽  
J. Michael McCaffery ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Secretory Pathway ◽  
Secretory Protein ◽  
Cellular Functions ◽  
Er Quality Control ◽  
Fluorescence And Electron Microscopy ◽  
The Unfolded Protein Response ◽  
Mutant Forms

The folding of nascent secretory and membrane proteins is monitored by the endoplasmic reticulum (ER) quality control system. Misfolded proteins are retained in the ER and can be removed by ER-associated degradation. As a model for the ER quality control of multispanning membrane proteins in yeast, we have been studying mutant forms of Ste6p. Here, we identify mislocalized mutant forms of Ste6p that induce the formation of, and localize to, prominent structures that are absent in normal cells. We have named these structures ER-associated compartments (ERACs), based on their juxtaposition to and connection with the ER, as observed by fluorescence and electron microscopy. ERACs comprise a network of tubulo-vesicular structures that seem to represent proliferated ER membranes. Resident ER lumenal and membrane proteins are present in ERACs in addition to their normal ER localization, suggesting there is no barrier for their entry into ERACs. However, the forms of Ste6p in ERACs are excluded from the ER and do not enter the secretory pathway; instead, they are ultimately targeted for ER-associated degradation. The presence of ERACs does not adversely affect secretory protein traffic through the ER and does not lead to induction of the unfolded protein response. We propose that ERACs may be holding sites to which misfolded membrane proteins are specifically diverted so as not to interfere with normal cellular functions. We discuss the likelihood that related ER membrane proliferations that form in response to certain other mutant or unassembled membrane proteins may be substantially similar to ERACs.

scholarly journals Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Benjamin M Adams ◽  
Nathan P Canniff ◽  
Kevin P Guay ◽  
Ida Signe Bohse Larsen ◽  
Daniel N Hebert
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Hek293 Cells ◽  
Substrate Selectivity ◽  
Early Secretory Pathway ◽  
Chaperone Binding ◽  
Chaperone Network ◽  
Insight Into ◽  
Lysosomal Proteins

UDP-glucose:glycoprotein glucosyltransferase (UGGT) 1 and 2 are central hubs in the chaperone network of the endoplasmic reticulum (ER), acting as gatekeepers to the early secretory pathway, yet little is known about their cellular clients. These two quality control sensors control lectin chaperone binding and glycoprotein egress from the ER. A quantitative glycoproteomics strategy was deployed to identify cellular substrates of the UGGTs at endogenous levels in CRISPR-edited HEK293 cells. The 71 UGGT substrates identified were mainly large multidomain and heavily glycosylated proteins when compared to the general N-glycoproteome. UGGT1 was the dominant glucosyltransferase with a preference toward large plasma membrane proteins whereas UGGT2 favored the modification of smaller, soluble lysosomal proteins. This study sheds light on differential specificities and roles of UGGT1 and UGGT2 and provides insight into the cellular reliance on the carbohydrate-dependent chaperone system to facilitate proper folding and maturation of the cellular N-glycoproteome.

scholarly journals Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

2020 ◽  
Author(s):  
Benjamin M. Adams ◽  
Nathan P. Canniff ◽  
Kevin P. Guay ◽  
Ida Signe Bohse Larsen ◽  
Daniel N. Hebert
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Hek293 Cells ◽  
Substrate Selectivity ◽  
Early Secretory Pathway ◽  
Chaperone Binding ◽  
Chaperone Network ◽  
Insight Into ◽  
Lysosomal Proteins

ABSTRACTUDP-glucose: glycoprotein glucosyltransferase (UGGT) 1 and 2 are central hubs in the chaperone network of the endoplasmic reticulum (ER), acting as gatekeepers to the early secretory pathway yet little is known about their cellular clients. These two quality control sensors control lectin chaperone binding and glycoprotein egress from ER. A quantitative glycoproteomics strategy was deployed to identify cellular substrates of the UGGTs at endogenous levels in CRISPR-edited HEK293 cells. The seventy-one UGGT substrates identified were mainly large multidomain and heavily glycosylated proteins when compared to the general N-glycome. UGGT1 was the dominant glucosyltransferase with a preference towards large plasma membrane proteins whereas UGGT2 favored the modification of smaller, soluble lysosomal proteins. This study sheds light on differential specificities and roles of UGGT1 and UGGT2 and provides insight into the cellular reliance on carbohydrate-dependent chaperone intervention by UGGT1 and UGGT2 to facilitate proper folding and maturation of the cellular N-glycome.

scholarly journals Zinc regulates ERp44-dependent protein quality control in the early secretory pathway

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Satoshi Watanabe ◽  
Yuta Amagai ◽  
Sara Sannino ◽  
Tiziana Tempio ◽  
Tiziana Anelli ◽  
...  
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Early Secretory Pathway ◽  
Dependent Protein

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 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.

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