scholarly journals OS-9 facilitates turnover of nonnative GRP94 marked by hyperglycosylation

2014 ◽  
Vol 25 (15) ◽  
pp. 2220-2234 ◽  
Author(s):  
Devin Dersh ◽  
Stephanie M. Jones ◽  
Davide Eletto ◽  
John C. Christianson ◽  
Yair Argon
Keyword(s):  
Quality Control ◽  
Molecular Chaperone ◽  
Protein Production ◽  
Tight Coupling ◽  
Er Quality Control ◽  
Folding Pathways ◽  
Client Proteins ◽  
Protein Folding Pathways ◽  
Glucose Regulated Protein

The tight coupling of protein folding pathways with disposal mechanisms promotes the efficacy of protein production in the endoplasmic reticulum (ER). It has been hypothesized that the ER-resident molecular chaperone glucose-regulated protein 94 (GRP94) is part of this quality control coupling because it supports folding of select client proteins yet also robustly associates with the lectin osteosarcoma amplified 9 (OS-9), a component involved in ER-associated degradation (ERAD). To explore this possibility, we investigated potential functions for the GRP94/OS-9 complex in ER quality control. Unexpectedly, GRP94 does not collaborate with OS-9 in ERAD of misfolded substrates, nor is the chaperone required directly for OS-9 folding. Instead, OS-9 binds preferentially to a subpopulation of GRP94 that is hyperglycosylated on cryptic N-linked glycan acceptor sites. Hyperglycosylated GRP94 forms have nonnative conformations and are less active. As a result, these species are degraded much faster than the major, monoglycosylated form of GRP94 in an OS-9–mediated, ERAD-independent, lysosomal-like mechanism. This study therefore clarifies the role of the GRP94/OS-9 complex and describes a novel pathway by which glycosylation of cryptic acceptor sites influences the function and fate of an ER-resident chaperone.

scholarly journals Role of calnexin in the ER quality control and productive folding of CFTR; differential effect of calnexin knockout on wild-type and ΔF508 CFTR

2008 ◽  
Vol 1783 (9) ◽  
pp. 1585-1594 ◽  
Author(s):  
Tsukasa Okiyoneda ◽  
Akiko Niibori ◽  
Kazutsune Harada ◽  
Taijun Kohno ◽  
Marek Michalak ◽  
...  
Keyword(s):  
Quality Control ◽  
Differential Effect ◽  
Wild Type ◽  
Er Quality Control ◽  
Δf508 Cftr

scholarly journals Fibrillary Glomerulonephritis and DnaJ Homolog Subfamily B Member 9 (DNAJB9)

Kidney360 ◽  
2020 ◽  
Vol 1 (9) ◽  
pp. 1002-1013
Author(s):  
Nattawat Klomjit ◽  
Mariam Priya Alexander ◽  
Ladan Zand
Keyword(s):  
Heat Shock Protein 70 ◽  
Poor Prognosis ◽  
Post Transplantation ◽  
Fibrillary Glomerulonephritis ◽  
Future Studies ◽  
Folding Pathways ◽  
Endoplasmic Reticulum Protein ◽  
Protein Folding Pathways ◽  
Prompt Diagnosis

Fibrillary GN (FGN) is a rare glomerular disease that is diagnosed based on the presence of fibrils in glomeruli. The fibrils are typically noncongophilic, randomly oriented, and measure 12–24 nm. Traditionally, electron microscopy (EM) has been an important tool to aid in the diagnosis of FGN by identifying the fibrils and to distinguish it from other entities that could mimic FGN. However, recently DnaJ homolog subfamily B member 9 (DNAJB9) has emerged as both a specific and sensitive biomarker in patients with FGN. It allows prompt diagnosis and alleviates reliance on EM. DNAJB9 is a cochaperone of heat shock protein 70 and is involved in endoplasmic reticulum protein-folding pathways. But its role in the pathogenesis of FGN remains elusive. DNAJB9 may act as a putative antigen or alternatively it may secondarily bind to misfolded IgG in the glomeruli. These hypotheses need future studies to elucidate the role of DNAJB9 in the pathogenesis of FGN. The treatment regimen for FGN has been limited due to paucity of studies. Most patients receive combination immunosuppressive regimens. Rituximab has been studied the most in FGN and it may delay disease progression. Prognosis of FGN remains poor and 50% require dialysis within 2 years of diagnosis. Despite its poor prognosis in native kidneys, the rate of recurrence post-transplantation is low (20%) and patient as well as allograft outcomes are similar to patients without FGN.

scholarly journals Role of the Lectin VIP36 in Post-ER Quality Control of Human α1-Antitrypsin

Traffic ◽  
2010 ◽  
Vol 11 (8) ◽  
pp. 1044-1055 ◽  
Author(s):  
Veronika Reiterer ◽  
Beat Nyfeler ◽  
Hans-Peter Hauri
Keyword(s):  
Quality Control ◽  
Er Quality Control

scholarly journals The role of UDP-Glc:glycoprotein glucosyltransferase 1 in the maturation of an obligate substrate prosaposin

2010 ◽  
Vol 189 (5) ◽  
pp. 829-841 ◽  
Author(s):  
Bradley R. Pearse ◽  
Taku Tamura ◽  
Johan C. Sunryd ◽  
Gregory A. Grabowski ◽  
Randal J. Kaufman ◽  
...  
Keyword(s):  
Quality Control ◽  
Molecular Chaperones ◽  
Control Factor ◽  
Dramatic Decrease ◽  
Er Quality Control ◽  
Basal Expression ◽  
Er Retention ◽  
Chaperone Binding ◽  
Quality Control Test

An endoplasmic reticulum (ER) quality control system assists in efficient folding and disposal of misfolded proteins. N-linked glycans are critical in these events because their composition dictates interactions with molecular chaperones. UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1) is a key quality control factor of the ER. It adds glucoses to N-linked glycans of nonglucosylated substrates that fail a quality control test, supporting additional rounds of chaperone binding and ER retention. How UGT1 functions in its native environment is poorly understood. The role of UGT1 in the maturation of glycoproteins at basal expression levels was analyzed. Prosaposin was identified as a prominent endogenous UGT1 substrate. A dramatic decrease in the secretion of prosaposin was observed in ugt1−/− cells with prosaposin localized to large juxtanuclear aggresome-like inclusions, which is indicative of its misfolding and the essential role that UGT1 plays in its proper maturation. A model is proposed that explains how UGT1 may aid in the folding of sequential domain–containing proteins such as prosaposin.

scholarly journals Interactions between intersubunit transmembrane domains regulate the chaperone-dependent degradation of an oligomeric membrane protein

2017 ◽  
Vol 474 (3) ◽  
pp. 357-376 ◽  
Author(s):  
Teresa M. Buck ◽  
Alexa S. Jordahl ◽  
Megan E. Yates ◽  
G. Michael Preston ◽  
Emily Cook ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Quality Control ◽  
Molecular Chaperone ◽  
Transmembrane Domain ◽  
The Other ◽  
Er Quality Control ◽  
Α Subunit ◽  
Domain Interactions ◽  
Immature Form ◽  
Epithelial Sodium Channel Enac

In the kidney, the epithelial sodium channel (ENaC) regulates blood pressure through control of sodium and volume homeostasis, and in the lung, ENaC regulates the volume of airway and alveolar fluids. ENaC is a heterotrimer of homologous α-, β- and γ-subunits, and assembles in the endoplasmic reticulum (ER) before it traffics to and functions at the plasma membrane. Improperly folded or orphaned ENaC subunits are subject to ER quality control and targeted for ER-associated degradation (ERAD). We previously established that a conserved, ER lumenal, molecular chaperone, Lhs1/GRP170, selects αENaC, but not β- or γ-ENaC, for degradation when the ENaC subunits were individually expressed. We now find that when all three subunits are co-expressed, Lhs1-facilitated ERAD was blocked. To determine which domain–domain interactions between the ENaC subunits are critical for chaperone-dependent quality control, we employed a yeast model and expressed chimeric α/βENaC constructs in the context of the ENaC heterotrimer. We discovered that the βENaC transmembrane domain was sufficient to prevent the Lhs1-dependent degradation of the α-subunit in the context of the ENaC heterotrimer. Our work also found that Lhs1 delivers αENaC for proteasome-mediated degradation after the protein has become polyubiquitinated. These data indicate that the Lhs1 chaperone selectively recognizes an immature form of αENaC, one which has failed to correctly assemble with the other channel subunits via its transmembrane domain.

The role of the ubiquitin–proteasome system in ER quality control

2005 ◽  
Vol 41 ◽  
pp. 99-112 ◽  
Author(s):  
Yihong Ye
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Mhc Class I ◽  
Heavy Chain ◽  
Ubiquitin Proteasome System ◽  
Cellular Proteins ◽  
Physiological Adaptation ◽  
Er Quality Control ◽  
Ubiquitin Proteasome

Misfolded endoplasmic reticulum (ER) proteins are eliminated by the retrotranslocation pathway in eukaryotes, which is an important physiological adaptation to ER stress. This pathway can be hijacked by certain viruses to destroy folded cellular proteins, such as MHC class I heavy chain. Recent studies have highlighted the importance of the ubiquitin–proteasome system (UPS) in this process.

scholarly journals AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity

2020 ◽  
Vol 29 (8) ◽  
pp. 1310-1318 ◽  
Author(s):  
Monica Aguilà ◽  
James Bellingham ◽  
Dimitra Athanasiou ◽  
Dalila Bevilacqua ◽  
Yanai Duran ◽  
...  
Keyword(s):  
Quality Control ◽  
Outer Nuclear Layer ◽  
Photoreceptor Cells ◽  
Er Quality Control ◽  
Full Field ◽  
Er Retention ◽  
Function Loss

Abstract Rhodopsin misfolding caused by the P23H mutation is a major cause of autosomal dominant retinitis pigmentosa (adRP). To date, there are no effective treatments for adRP. The BiP co-chaperone and reductase ERdj5 (DNAJC10) is part of the endoplasmic reticulum (ER) quality control machinery, and previous studies have shown that overexpression of ERdj5 in vitro enhanced the degradation of P23H rhodopsin, whereas knockdown of ERdj5 increased P23H rhodopsin ER retention and aggregation. Here, we investigated the role of ERdj5 in photoreceptor homeostasis in vivo by using an Erdj5 knockout mouse crossed with the P23H knock-in mouse and by adeno-associated viral (AAV) vector-mediated gene augmentation of ERdj5 in P23H-3 rats. Electroretinogram (ERG) and optical coherence tomography of Erdj5−/− and P23H+/−:Erdj5−/− mice showed no effect of ERdj5 ablation on retinal function or photoreceptor survival. Rhodopsin levels and localization were similar to those of control animals at a range of time points. By contrast, when AAV2/8-ERdj5-HA was subretinally injected into P23H-3 rats, analysis of the full-field ERG suggested that overexpression of ERdj5 reduced visual function loss 10 weeks post-injection (PI). This correlated with a significant preservation of photoreceptor cells at 4 and 10 weeks PI. Assessment of the outer nuclear layer (ONL) morphology showed preserved ONL thickness and reduced rhodopsin retention in the ONL in the injected superior retina. Overall, these data suggest that manipulation of the ER quality control and ER-associated degradation factors to promote mutant protein degradation could be beneficial for the treatment of adRP caused by mutant rhodopsin.

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