Endoplasmic reticulum quality control and dysmyelination

AbstractDysmyelination contributes to several human diseases including multiple sclerosis, Charcot-Marie-Tooth, leukodystrophies, and schizophrenia and can result in serious neurological disability. Properly formed, compacted myelin sheaths are required for appropriate nerve conduction velocities and the health and survival of neurons. Many different molecular mechanisms contribute to dysmyelination and many of these mechanisms originate at the level of the endoplasmic reticulum. The endoplasmic reticulum is a critical organelle for myelin biosynthesis and maintenance as the site of myelin protein folding quality control, Ca2+ homeostasis, cholesterol biosynthesis, and modulation of cellular stress. This review paper highlights the role of the endoplasmic reticulum and its resident molecules as an upstream and dynamic contributor to myelin and myelin pathologies.

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Investigating the role of ERAD on antibody processing in glycoengineered Saccharomyces cerevisiae

FEMS Yeast Research ◽

10.1093/femsyr/foaa002 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Mari A Piirainen ◽

Alexander D Frey

Keyword(s):

Saccharomyces Cerevisiae ◽

Quality Control ◽

Endoplasmic Reticulum ◽

Heavy Chain ◽

Chain Molecules ◽

Secretion Signal ◽

Endoplasmic Reticulum Associated Degradation ◽

Endoplasmic Reticulum Quality Control ◽

Therapeutic Glycoproteins

ABSTRACT N-glycosylation plays an important role in the endoplasmic reticulum quality control (ERQC). N-glycan biosynthesis pathways have been engineered in yeasts and fungi to enable the production of therapeutic glycoproteins with human-compatible N-glycosylation, and some glycoengineering approaches alter the synthesis of the lipid-linked oligosaccharide (LLO). Because the effects of LLO engineering on ERQC are currently unknown, we characterized intracellular processing of IgG in glycoengineered Δalg3 Δalg11 Saccharomyces cerevisiae strain and analyzed how altered LLO structures affect endoplasmic reticulum-associated degradation (ERAD). Intracellular IgG light and heavy chain molecules expressed in Δalg3 Δalg11 strain are ERAD substrates and targeted to ERAD independently of Yos9p and Htm1p, whereas in the presence of ALG3 ERAD targeting is dependent on Yos9p but does not require Htm1p. Blocking of ERAD accumulated ER and post-Golgi forms of IgG and increased glycosylation of matα secretion signal but did not improve IgG secretion. Our results show ERAD targeting of a heterologous glycoprotein in yeast, and suggest that proteins in the ER can be targeted to ERAD via other mechanisms than the Htm1p-Yos9p-dependent route when the LLO biosynthesis is altered.

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Specific ER quality control components required for biogenesis of the plant innate immune receptor EFR

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0905532106 ◽

2009 ◽

Vol 106 (37) ◽

pp. 15973-15978 ◽

Cited By ~ 160

Author(s):

Jing Li ◽

Chu Zhao-Hui ◽

Martine Batoux ◽

Vladimir Nekrasov ◽

Milena Roux ◽

...

Keyword(s):

Innate Immunity ◽

Quality Control ◽

Molecular Mechanisms ◽

Plant Innate Immunity ◽

Er Quality Control ◽

Multiple Alleles ◽

Specific Subset ◽

Endoplasmic Reticulum Quality Control ◽

Molecular Patterns

Plant innate immunity depends in part on recognition of pathogen-associated molecular patterns (PAMPs), such as bacterial flagellin, EF-Tu, and fungal chitin. Recognition is mediated by pattern-recogntition receptors (PRRs) and results in PAMP-triggered immunity. EF-Tu and flagellin, and the derived peptides elf18 and flg22, are recognized in Arabidopsis by the leucine-rich repeat receptor kinases (LRR-RK), EFR and FLS2, respectively. To gain insights into the molecular mechanisms underlying PTI, we investigated EFR-mediated PTI using genetics. A forward-genetic screen for Arabidopsis elf18-insensitive (elfin) mutants revealed multiple alleles of calreticulin3 (CRT3), UDP-glucose glycoprotein glucosyl transferase (UGGT), and an HDEL receptor family member (ERD2b), potentially involved in endoplasmic reticulum quality control (ER-QC). Strikingly, FLS2-mediated responses were not impaired in crt3, uggt, and erd2b null mutants, revealing that the identified mutations are specific to EFR. A crt3 null mutant did not accumulate EFR protein, suggesting that EFR is a substrate for CRT3. Interestingly, Erd2b did not accumulate CRT3 protein, although they accumulate wild-type levels of other ER proteins. ERD2B seems therefore to be a specific HDEL receptor for CRT3 that allows its retro-translocation from the Golgi to the ER. These data reveal a previously unsuspected role of a specific subset of ER-QC machinery components for PRR accumulation in plant innate immunity.

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Oligosaccharide-based Information in Endoplasmic Reticulum Quality Control and Other Biological Systems

Journal of Biological Chemistry ◽

10.1074/jbc.r100002200 ◽

2001 ◽

Vol 276 (12) ◽

pp. 8623-8626 ◽

Cited By ~ 46

Author(s):

Mark A. Lehrman

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Biological Systems ◽

Endoplasmic Reticulum Quality Control

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Endoplasmic reticulum quality control and congenital pathology

Journal of Applied Biomedicine ◽

10.32725/jab.2005.021 ◽

2005 ◽

Vol 3 (4) ◽

pp. 159-165

Author(s):

Marek Michalak

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Quality Control

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Nox4 Mediates RANKL-induced ER-Phagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway

10.21203/rs.3.rs-34288/v1 ◽

2020 ◽

Author(s):

Jing Sun ◽

wugui chen ◽

Songtao Li ◽

Sizhen Yang ◽

Ying Zhang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Bone Resorption ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Nuclear Factor Κb ◽

Protein Levels ◽

Unfolded Protein ◽

Regulatory Effects ◽

Protein Response

Abstract Background: Receptor activator of nuclear factor-κB ligand (RANKL) has been found to induce osteoclastogenesis and bone resorption. However, the underlying molecular mechanisms remain unclear. Methods: Osteoclastogenesis was evaluated by number of TRAP-positive multinuclear (≥3) osteoclasts, bone resorption pits and expression levels of related genes. Autophagy activity were evaluated by LC3-II/LC3-I ratio, number of autophagic vacuoles and adenovirus-mRFP-GFP-tagged LC3 reporting system; Inhibitor chloroquine (CQ) was used to verified the role of autophagy in RANKL-induced osteoclastogenesis; Via downregulating Nox4 with inhibitor (DPI) and retrovirus-conveyed shRNA, we further explored the importance of Nox4 in RANKL-induced autophagy and osteoclastogenesis, as well as the regulatory effects of Nox4 on nonmitochondrial reactive oxygen species (ROS) and PERK/eIF-2α/ATF4 pathway. Intracellular ROS scavenger (NAC), mitochondrial-targeted antioxidant (MitoTEMPO) and inhibitor of PERK (GSK2606414) were also employed to investigate the role of ROS and PERK/eIF-2α/ATF4 pathway in RANKL-induced autophagy and osteoclastogenesis. Results: RANKL markedly increased autophagy, while CQ treatment caused reduction of RANKL-induced autophagy and osteoclastogenesis. Consistent with the increased autophagy, the protein levels of Nox4 were significantly increased, and Nox4 was selectively localized within the endoplasmic reticulum (ER) after RANKL stimulation. DPI and shRNA efficiently decreased the protein level and (or) activity of Nox4 in the ER and inhibited RANKL-induced autophagy and osteoclastogenesis. Mechanistically, we found that Nox4 regulates RANKL-induced autophagy activation and osteoclastogenesis by stimulating the production of nonmitochondrial ROS. Additionally, Nox4-derived nonmitochondrial ROS dramatically activate PERK/eIF-2α/ATF4, which is a critical unfolded protein response (UPR)-related signaling pathway during ER stress. Blocking the activation of the PERK/eIF-2α/ATF4 signaling pathway either by Nox4 shRNA, ROS antioxidant or PERK inhibitor (GSK2606414) treatment significantly inhibited endoplasmic reticulum autophagy (ER-phagy) during RANKL-induced osteoclastogenesis. Conclusions: Our findings provide new insights into the processes of RANKL-induced osteoclastogenesis and will help the development of new therapeutic strategies for osteoclastogenesis-related diseases.

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Mechanism of Class 1 (Glycosylhydrolase Family 47) α-Mannosidases Involved inN-Glycan Processing and Endoplasmic Reticulum Quality Control

Journal of Biological Chemistry ◽

10.1074/jbc.m500119200 ◽

2005 ◽

Vol 280 (16) ◽

pp. 16197-16207 ◽

Cited By ~ 89

Author(s):

Khanita Karaveg ◽

Aloysius Siriwardena ◽

Wolfram Tempel ◽

Zhi-Jie Liu ◽

John Glushka ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Bond Cleavage ◽

Substrate Analog ◽

Acid And Base ◽

Class 1 ◽

Glycoside Bond ◽

Endoplasmic Reticulum Quality Control ◽

Mutant Forms ◽

Hydrolytic Mechanism

Quality control in the endoplasmic reticulum (ER) determines the fate of newly synthesized glycoproteins toward either correct folding or disposal by ER-associated degradation. Initiation of the disposal process involves selective trimming ofN-glycans attached to misfolded glycoproteins by ER α-mannosidase I and subsequent recognition by the ER degradation-enhancing α-mannosidase-like protein family of lectins, both members of glycosylhydrolase family 47. The unusual inverting hydrolytic mechanism catalyzed by members of this family is investigated here by a combination of kinetic and binding analyses of wild type and mutant forms of human ER α-mannosidase I as well as by structural analysis of a co-complex with an uncleaved thiodisaccharide substrate analog. These data reveal the roles of potential catalytic acid and base residues and the identification of a novel3S1sugar conformation for the bound substrate analog. The co-crystal structure described here, in combination with the1C4conformation of a previously identified co-complex with the glycone mimic, 1-deoxymannojirimycin, indicates that glycoside bond cleavage proceeds through a least motion conformational twist of a properly predisposed substrate in the –1 subsite. A novel3H4conformation is proposed as the exploded transition state.

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