scholarly journals Posttranscriptional Regulation of Glycoprotein Quality Control in the Endoplasmic Reticulum Is Controlled by the E2 Ub-Conjugating Enzyme UBC6e

2016 ◽  
Vol 63 (5) ◽  
pp. 753-767 ◽  
Author(s):  
Masatoshi Hagiwara ◽  
Jingjing Ling ◽  
Paul-Albert Koenig ◽  
Hidde L. Ploegh
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Posttranscriptional Regulation ◽  
Glycoprotein Quality Control ◽  
Conjugating Enzyme

scholarly journals In Vivo Action of the HRD Ubiquitin Ligase Complex: Mechanisms of Endoplasmic Reticulum Quality Control and Sterol Regulation

2001 ◽  
Vol 21 (13) ◽  
pp. 4276-4291 ◽  
Author(s):  
Richard G. Gardner ◽  
Alexander G. Shearer ◽  
Randolph Y. Hampton
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Sequence Similarity ◽  
High Specificity ◽  
Specific Sequence ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

ABSTRACT Ubiquitination is used to target both normal proteins for specific regulated degradation and misfolded proteins for purposes of quality control destruction. Ubiquitin ligases, or E3 proteins, promote ubiquitination by effecting the specific transfer of ubiquitin from the correct ubiquitin-conjugating enzyme, or E2 protein, to the target substrate. Substrate specificity is usually determined by specific sequence determinants, or degrons, in the target substrate that are recognized by the ubiquitin ligase. In quality control, however, a potentially vast collection of proteins with characteristic hallmarks of misfolding or misassembly are targeted with high specificity despite the lack of any sequence similarity between substrates. In order to understand the mechanisms of quality control ubiquitination, we have focused our attention on the first characterized quality control ubiquitin ligase, the HRD complex, which is responsible for the endoplasmic reticulum (ER)-associated degradation (ERAD) of numerous ER-resident proteins. Using an in vivo cross-linking assay, we directly examined the association of the separate HRDcomplex components with various ERAD substrates. We have discovered that the HRD ubiquitin ligase complex associates with both ERAD substrates and stable proteins, but only mediates ubiquitin-conjugating enzyme association with ERAD substrates. Our studies with the sterol pathway-regulated ERAD substrate Hmg2p, an isozyme of the yeast cholesterol biosynthetic enzyme HMG-coenzyme A reductase (HMGR), indicated that the HRD complex discerns between a degradation-competent “misfolded” state and a stable, tightly folded state. Thus, it appears that the physiologically regulated, HRD-dependent degradation of HMGR is effected by a programmed structural transition from a stable protein to a quality control substrate.

scholarly journals Endoplasmic Reticulum Glycoprotein Quality Control Regulates CD1d Assembly and CD1d-mediated Antigen Presentation

2013 ◽  
Vol 288 (23) ◽  
pp. 16391-16402 ◽  
Author(s):  
Amit Kunte ◽  
Wei Zhang ◽  
Crina Paduraru ◽  
Natacha Veerapen ◽  
Liam R. Cox ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control Process ◽  
Adaptive Immune ◽  
Histocompatibility Complex ◽  
Quality Control Process ◽  
Exogenous Antigen ◽  
And Function ◽  
Glycoprotein Quality Control

The non-classical major histocompatibility complex (MHC) homologue CD1d presents lipid antigens to innate-like lymphocytes called natural-killer T (NKT) cells. These cells, by virtue of their broad cytokine repertoire, shape innate and adaptive immune responses. Here, we have assessed the role of endoplasmic reticulum glycoprotein quality control in CD1d assembly and function, specifically the role of a key component of the quality control machinery, the enzyme UDP glucose glycoprotein glucosyltransferase (UGT1). We observe that in UGT1-deficient cells, CD1d associates prematurely with β2-microglobulin (β2m) and is able to rapidly exit the endoplasmic reticulum. At least some of these CD1d-β2m heterodimers are shorter-lived and can be rescued by provision of a defined exogenous antigen, α-galactosylceramide. Importantly, we show that in UGT1-deficient cells the CD1d-β2m heterodimers have altered antigenicity despite the fact that their cell surface levels are unchanged. We propose that UGT1 serves as a quality control checkpoint during CD1d assembly and further suggest that UGT1-mediated quality control can shape the lipid repertoire of newly synthesized CD1d. The quality control process may play a role in ensuring stability of exported CD1d-β2m complexes, in facilitating presentation of low abundance high affinity antigens, or in preventing deleterious responses to self lipids.

scholarly journals Reconstructed glycan profile for evaluation of operating status of the endoplasmic reticulum glycoprotein quality control

Glycobiology ◽  
2012 ◽  
Vol 23 (1) ◽  
pp. 121-131 ◽  
Author(s):  
S. Iwamoto ◽  
M. Isoyama ◽  
M. Hirano ◽  
K. Yamaya ◽  
Y. Ito ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Glycan Profile ◽  
Glycoprotein Quality Control

scholarly journals Role of malectin in Glc2Man9GlcNAc2-dependent quality control of α1-antitrypsin

2011 ◽  
Vol 22 (19) ◽  
pp. 3559-3570 ◽  
Author(s):  
Yang Chen ◽  
Dan Hu ◽  
Rikio Yabe ◽  
Hiroaki Tateno ◽  
Sheng-Ying Qin ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Structural Similarity ◽  
Metabolic Labeling ◽  
Wild Type ◽  
Binding Assays ◽  
Mrna Transcription ◽  
Glycoprotein Quality Control

Malectin was first discovered as a novel endoplasmic reticulum (ER)–resident lectin from Xenopus laevis that exhibits structural similarity to bacterial glycosylhydrolases. Like other intracellular lectins involved in glycoprotein quality control, malectin is highly conserved in animals. Here results from in vitro membrane-based binding assays and frontal affinity chromatography confirm that human malectin binds specifically to Glc2Man9GlcNAc2 (G2M9) N-glycan, with a Ka of 1.97 × 105 M−1, whereas binding to Glc1Man9GlcNAc2 (G1M9), Glc3Man9GlcNAc2 (G3M9), and other N-glycans is barely detectable. Metabolic labeling and immunoprecipitation experiments demonstrate that before entering the calnexin cycle, the folding-defective human α1-antitrypsin variant null Hong Kong (ATNHK) stably associates with malectin, whereas wild-type α1-antitrypsin (AT) or N-glycan–truncated variant of ATNHK (ATNHK-Q3) dose not. Moreover, malectin overexpression dramatically inhibits the secretion of ATNHK through a mechanism that involves enhanced ER-associated protein degradation; by comparison, the secretion of AT and ATNHK-Q3 is only slightly affected by malectin overexpression. ER-stress induced by tunicamycin results in significantly elevated mRNA transcription of malectin. These observations suggest a possible role of malectin in regulating newly synthesized glycoproteins via G2M9 recognition.

scholarly journals Glycoprotein Quality Control in the Endoplasmic Reticulum

2001 ◽  
Vol 276 (16) ◽  
pp. 12885-12892 ◽  
Author(s):  
Claudio Fagioli ◽  
Roberto Sitia
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Glycoprotein Quality Control

scholarly journals Glycoprotein Quality Control and Endoplasmic Reticulum Stress

Molecules ◽  
2015 ◽  
Vol 20 (8) ◽  
pp. 13689-13704 ◽  
Author(s):  
Qian Wang ◽  
Jody Groenendyk ◽  
Marek Michalak
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Glycoprotein Quality Control

scholarly journals Mammalian ER mannosidase I resides in quality control vesicles, where it encounters its glycoprotein substrates

2015 ◽  
Vol 26 (2) ◽  
pp. 172-184 ◽  
Author(s):  
Ron Benyair ◽  
Navit Ogen-Shtern ◽  
Niv Mazkereth ◽  
Ben Shai ◽  
Marcelo Ehrlich ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Steady State ◽  
Golgi Apparatus ◽  
Central Component ◽  
Er Quality Control ◽  
Autophagic Process ◽  
Sugar Chains ◽  
Control Compartment ◽  
Glycoprotein Quality Control

Endoplasmic reticulum α1,2 mannosidase I (ERManI), a central component of ER quality control and ER-associated degradation (ERAD), acts as a timer enzyme, modifying N-linked sugar chains of glycoproteins with time. This process halts glycoprotein folding attempts when necessary and targets terminally misfolded glycoproteins to ERAD. Despite the importance of ERManI in maintenance of glycoprotein quality control, fundamental questions regarding this enzyme remain controversial. One such question is the subcellular localization of ERManI, which has been suggested to localize to the ER membrane, the ER-derived quality control compartment (ERQC), and, surprisingly, recently to the Golgi apparatus. To try to clarify this controversy, we applied a series of approaches that indicate that ERManI is located, at the steady state, in quality control vesicles (QCVs) to which ERAD substrates are transported and in which they interact with the enzyme. Both endogenous and exogenously expressed ERManI migrate at an ER-like density on iodixanol gradients, suggesting that the QCVs are derived from the ER. The QCVs are highly mobile, displaying dynamics that are dependent on microtubules and COP-II but not on COP-I vesicle machinery. Under ER stress conditions, the QCVs converge in a juxtanuclear region, at the ERQC, as previously reported. Our results also suggest that ERManI is turned over by an active autophagic process. Of importance, we found that membrane disturbance, as is common in immunofluorescence methods, leads to an artificial appearance of ERManI in a Golgi pattern.

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