Participation of lectin chaperones and thiol oxidoreductases in protein folding within the endoplasmic reticulum

Protein synthesis, folding and degradation functions are spatially segregated in the endoplasmic reticulum (ER) with respect to the membrane and the ribosome (rough and smooth ER). Interrogation of a proteomics resource characterizing rough and smooth ER membranes subfractionated into cytosolic, membrane, and soluble fractions gives a spatial map of known proteins involved in ER function. The spatial localization of 224 identified unknown proteins in the ER is predicted to give insight into their function. Here we provide evidence that the proteomics resource accurately predicts the function of new proteins involved in protein synthesis (nudilin), protein translocation across the ER membrane (nicalin), co-translational protein folding (stexin), and distal protein folding in the lumen of the ER (erlin-1, TMX2). Proteomics provides the spatial localization of proteins and can be used to accurately predict protein function.

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Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-212673 ◽

2021 ◽

pp. 1-10

Author(s):

Vera Kovaleva ◽

Mart Saarma

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Endoplasmic Reticulum ◽

Protein Folding ◽

Er Stress ◽

Protein Misfolding ◽

Drug Targets ◽

Dopamine Neurons ◽

Drug Candidates ◽

The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

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Cadmium impairs protein folding in the endoplasmic reticulum and induces the unfolded protein response

FEMS Yeast Research ◽

10.1093/femsyr/fow049 ◽

2016 ◽

Vol 16 (5) ◽

pp. fow049 ◽

Cited By ~ 20

Author(s):

Quynh Giang Le ◽

Yuki Ishiwata-Kimata ◽

Kenji Kohno ◽

Yukio Kimata

Keyword(s):

Endoplasmic Reticulum ◽

Protein Folding ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

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Limited ER quality control for GPI-anchored proteins

The Journal of Cell Biology ◽

10.1083/jcb.201602010 ◽

2016 ◽

Vol 213 (6) ◽

pp. 693-704 ◽

Cited By ~ 22

Author(s):

Natalia Sikorska ◽

Leticia Lemus ◽

Auxiliadora Aguilera-Romero ◽

Javier Manzano-Lopez ◽

Howard Riezman ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Protein Folding ◽

Misfolded Proteins ◽

Control Mechanisms ◽

Gpi Anchor ◽

Er Quality Control ◽

Entire Class ◽

Er Export ◽

Export Signal

Endoplasmic reticulum (ER) quality control mechanisms target terminally misfolded proteins for ER-associated degradation (ERAD). Misfolded glycophosphatidylinositol-anchored proteins (GPI-APs) are, however, generally poor ERAD substrates and are targeted mainly to the vacuole/lysosome for degradation, leading to predictions that a GPI anchor sterically obstructs ERAD. Here we analyzed the degradation of the misfolded GPI-AP Gas1* in yeast. We could efficiently route Gas1* to Hrd1-dependent ERAD and provide evidence that it contains a GPI anchor, ruling out that a GPI anchor obstructs ERAD. Instead, we show that the normally decreased susceptibility of Gas1* to ERAD is caused by canonical remodeling of its GPI anchor, which occurs in all GPI-APs and provides a protein-independent ER export signal. Thus, GPI anchor remodeling is independent of protein folding and leads to efficient ER export of even misfolded species. Our data imply that ER quality control is limited for the entire class of GPI-APs, many of them being clinically relevant.

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Endoplasmic reticulum stress in lung disease

European Respiratory Review ◽

10.1183/16000617.0018-2017 ◽

2017 ◽

Vol 26 (144) ◽

pp. 170018 ◽

Cited By ~ 22

Author(s):

Stefan J. Marciniak

Keyword(s):

Endoplasmic Reticulum ◽

Protein Folding ◽

Pulmonary Fibrosis ◽

Endoplasmic Reticulum Stress ◽

Lung Disease ◽

Cigarette Smoke ◽

Protein Misfolding ◽

Fine Particulates ◽

Disease Protein

Exposure to inhaled pollutants, including fine particulates and cigarette smoke is a major cause of lung disease in Europe. While it is established that inhaled pollutants have devastating effects on the genome, it is now recognised that additional effects on protein folding also drive the development of lung disease. Protein misfolding in the endoplasmic reticulum affects the pathogenesis of many diseases, ranging from pulmonary fibrosis to cancer. It is therefore important to understand how cells respond to endoplasmic reticulum stress and how this affects pulmonary tissues in disease. These insights may offer opportunities to manipulate such endoplasmic reticulum stress pathways and thereby cure lung disease.

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Characterization of the endoplasmic reticulum–resident peroxidases GPx7 and GPx8 shows the higher oxidative activity of GPx7 and its linkage to oxidative protein folding

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013607 ◽

2020 ◽

Vol 295 (36) ◽

pp. 12772-12785 ◽

Cited By ~ 1

Author(s):

Shingo Kanemura ◽

Elza Firdiani Sofia ◽

Naoya Hirai ◽

Masaki Okumura ◽

Hiroshi Kadokura ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Protein Folding ◽

Physiological Role ◽

High Reactivity ◽

Oxidation Activity ◽

Formation Pathway ◽

Oxidative Protein Folding ◽

Redox Active ◽

Protein Disulfide

Oxidative protein folding occurs primarily in the mammalian endoplasmic reticulum, enabled by a diverse network comprising more than 20 members of the protein disulfide isomerase (PDI) family and more than five PDI oxidases. Although the canonical disulfide bond formation pathway involving Ero1α and PDI has been well-studied so far, the physiological roles of the newly identified PDI oxidases, glutathione peroxidase-7 (GPx7) and -8 (GPx8), are only poorly understood. We here demonstrated that human GPx7 has much higher reactivity with H2O2 and hence greater PDI oxidation activity than human GPx8. The high reactivity of GPx7 is due to the presence of a catalytic tetrad at the redox-active site, which stabilizes the sulfenylated species generated upon the reaction with H2O2. Although it was previously postulated that GPx7 catalysis involved a highly reactive peroxidatic cysteine that can be sulfenylated by H2O2, we revealed that a resolving cysteine instead regulates the PDI oxidation activity of GPx7. We also determined that GPx7 formed complexes preferentially with PDI and P5 in H2O2-treated cells. Altogether, these results suggest that human GPx7 functions as an H2O2-dependent PDI oxidase in cells, whereas PDI oxidation may not be the central physiological role of human GPx8.

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