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Protein folding in the ER

Yongchao Wang, Xin Wang, Hui Li, Mei Xu, Jacqueline Frank, Jia Luo
Alcohol abuse causes brain damage and cognitive dysfunction. However, the underlying mechanisms remain elusive. Endoplasmic reticulum (ER) acts as machinery to ensure the proper folding of newly synthesized proteins. The perturbation of ER, i.e., ER stress, plays a pivotal role in some neurological disorders. Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is involved in the regulation of ER stress. The current study sought to determine whether binge ethanol exposure induces ER stress in adult mouse brain and the role mTOR signaling during this process...
August 13, 2018: Toxicology and Applied Pharmacology
Xiaofei Song, Yuanzi Li, Yuzhen Wu, Miao Cai, Quanli Liu, Kai Gao, Xiuming Zhang, Yanling Bai, Haijin Xu, Mingqiang Qiao
As a traditional ethanol-producing microorganism, Saccharomyces cerevisiae is an ideal host for consolidated bioprocessing (CBP). However, expression of heterologous cellulase increases the metabolic burden in yeast, which results in low cellulase activity and poor cellulose degradation efficiency. In this study, cellulase-expressing yeast strains that could efficiently degrade different cellulosic substrates were created by optimizing cellulase ratios through a POT1-mediated δ-integration strategy. Metabolic engineering strategies, including optimization of codon usage, promoter and signal peptide were also included in this system...
August 13, 2018: FEMS Yeast Research
Lihong Tian, Yanping Xing, Masako Fukuda, Rong Li, Toshihiro Kumamaru, Dandan Qian, Xiangbai Dong, Le Qing Qu
Rice glutelins are initially synthesized as 57-kDa precursors at the endoplasmic reticulum (ER) and finally transported into protein storage vacuole. However, the sequence motifs that affect proglutelins folding, assembly and exiting from ER remain poorly defined. In this study, we characterized a mutant with nine amino acids deleted in the GluA2 protein, which resulted in specific accumulation of GluA precursor. The deleted amino acids constitute a well-conserved sequence (LVYIIQGRG) in glutelins and all residues in this motif are necessary for ER export of GluA2...
August 10, 2018: Journal of Experimental Botany
Sun-Ji Park, Yeawon Kim, Ying Maggie Chen
The advent of next-generation sequencing (NGS) in recent years has led to a rapid discovery of novel or rare genetic variants in human kidney cell genes, which is transforming the risk assessment, diagnosis, and treatment of kidney disease. Mutations may lead to protein misfolding, disruption of protein trafficking, and endoplasmic reticulum (ER) retention. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and unfolded protein response. Mutations in nephrin (NPHS1), podocin (NPHS2), laminin β2 (LAMB2), and α-actinin-4 (ACTN4) have been shown to induce ER stress in HEK293 cells and podocytes in hereditary nephrotic syndromes; various founder mutations in collagen IV α chains (COL4A) have been demonstrated to activate podocyte ER stress in collagen IV nephropathies; and mutations in uromodulin (UMOD) have been reported to trigger tubular ER stress in autosomal dominant tubulointerstitial kidney disease...
August 11, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Wei-Hwa Lee, Li-Ching Chen, Chia-Jung Lee, Chi-Cheng Huang, Yuan-Soon Ho, Po-Sheng Yang, Chi-Tang Ho, Hang-Lung Chang, I-Hsuan Lin, Hui-Wen Chang, Yun-Ru Liu, Chih-Hsiung Wu, Shih-Hsin Tu
The DNA primase polypeptide 1 (PRIM1) is responsible for synthesizing small RNA primers for Okazaki fragments generated during discontinuous DNA replication. PRIM1 mRNA expression levels in breast tumor samples were detected by real-time PCR analysis. Xenografted tumor model was established to study the carcinogenic role of PRIM1 and its potential therapeutic applications. The average PRIM1 mRNA (copy number x 103 /μg) expression was 4.7-fold higher in tumors than in normal tissue (*p = 0.005, n = 254). PRIM1 was detected preferentially at a higher level (> 40-fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0...
August 11, 2018: International Journal of Cancer. Journal International du Cancer
Yu-Huei Liu, Yui-Ping Weng, Hsin-Ying Tsai, Chao-Jung Chen, Der-Yen Lee, Ching-Liang Hsieh, Yang-Chang Wu, Jung-Yaw Lin
BACKGROUND: Pancreatic cancer (PC) remains the leading cause of cancer mortality, with limited therapeutic targets, and alterations in endoplasmic reticulum (ER)-related proteostasis may be a potential target for therapy. The root bark of Paeonia suffruticosa has been shown to inhibit cancer growth and metastasis, although its impact on PC is unknown. PURPOSE: To ascertain the anti-cancer effects of P. suffruticosa on oncogenic functions of PC and determine the detailed molecular mechanisms...
July 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Yukihiro Nagashima, Antje von Schaewen, Hisashi Koiwa
Protein N-glycosylation is one of the major post-translational modifications in eukaryotic cells. In lower unicellular eukaryotes, the known functions of N-glycans are predominantly in protein folding and quality control within the lumen of the endoplasmic reticulum (ER). In multicellular organisms, complex N-glycans are important for developmental programs and immune responses. However, little is known about the functions of complex N-glycans in plants. Formed in the Golgi apparatus, plant complex N-glycans have structures distinct from their animal counterparts due to a set of glycosyltransferases unique to plants...
September 2018: Plant Science: An International Journal of Experimental Plant Biology
Xiaoli Geng, Xinshan Zang, Haoran Li, Zhenshan Liu, Aiju Zhao, Jian Liu, Huiru Peng, Yingyin Yao, Zhaorong Hu, Zhongfu Ni, Qixin Sun, Mingming Xin
Conditions that disrupt protein folding, such as heat stress, can overwhelm the capacity of cells to fold proteins, thus causing endoplasmic reticulum (ER) stress. In Arabidopsis thaliana and other plants, inositol-requiring enzyme-1 mediated unconventional splicing of bZIP60 plays a crucial role in the heat and ER stress responses. However, little is known about this pathway in wheat (Triticum aestivum), especially its importance in heat tolerance. Here, we found that heat stress induced upregulation and unconventional splicing of TabZIP60 occurred in wheat seedlings...
September 2018: Plant Science: An International Journal of Experimental Plant Biology
Jae-Seon So
The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, folding and modification, and lipid synthesis and calcium storage. Dysregulation of ER functions leads to the accumulation of misfolded- or unfolded-protein in the ER lumen, and this triggers the unfolded protein response (UPR), which restores ER homeostasis. The UPR is characterized by three distinct downstream signaling pathways that promote cell survival or apoptosis depending on the stressor, the intensity and duration of ER stress, and the cell type...
July 30, 2018: Molecules and Cells
Jinqiang Huang, Yongjuan Li, Zhe Liu, Yujun Kang, Jianfu Wang
Rainbow trout (Oncorhynchus mykiss) are widely cultured throughout the word for commercial aquaculture. However, as a cold-water species, rainbow trout are highly susceptible to heat stress, which may cause pathological signs or diseases by alleviating the immune roles and then lead to mass mortality. Understanding the molecular mechanisms that occur in the rainbow trout in response to heat stress will be useful to decrease heat stress-related morbidity and mortality in trout aquaculture. In the present study, we conducted transcriptome analysis of head kidney tissue in rainbow trout under heat-stress (24 °C) and control (18 °C) conditions, to identify heat stress-induced genes and pathways...
August 2, 2018: Fish & Shellfish Immunology
Roberto Covino, Gerhard Hummer, Robert Ernst
Eukaryotic cells face the challenge of maintaining the complex composition of several coexisting organelles. The molecular mechanisms underlying the homeostasis of subcellular membranes and their adaptation during stress are only now starting to emerge. Here, we discuss three membrane property sensors of the endoplasmic reticulum (ER), namely OPI1, MGA2, and IRE1, each controlling a large cellular program impacting the lipid metabolic network. OPI1 coordinates the production of membrane and storage lipids, MGA2 regulates the production of unsaturated fatty acids required for membrane biogenesis, and IRE1 controls the unfolded protein response (UPR) to adjust ER size, protein folding, and the secretory capacity of the cell...
August 2, 2018: Molecular Cell
Adam M Benham
The Endoplasmic Reticulum (ER) is the major site for secretory protein production in eukaryotic cells and like an efficient factory, it has the capacity to expand or contract its output depending on the demand for its services. A primary function of the ER is to co-ordinate the quality control of proteins as they enter this folding factory at the base of the secretory pathway. Reduction-oxidation (redox) reactions have an important role to play in the quality control process, through the provision of disulphide bonds and by maintaining a favourable redox environment for oxidative protein folding...
July 31, 2018: FEBS Journal
Jiwon Hwang, Ling Qi
Endoplasmic reticulum (ER)-associated degradation (ERAD) and the unfolded protein response (UPR) are two key quality-control machineries in the cell. ERAD is responsible for the clearance of misfolded proteins in the ER for cytosolic proteasomal degradation, while UPR is activated in response to the accumulation of misfolded proteins. It has long been thought that ERAD is an integral part of UPR because expression of many ERAD genes is controlled by UPR; however, recent studies have suggested that ERAD has a direct role in controlling the protein turnover and abundance of IRE1α, the most conserved UPR sensor...
August 2018: Trends in Biochemical Sciences
Raji Lenin, Peter G Nagy, Shanta Alli, Vidhya R Rao, Matthias A Clauss, Uday B Kompella, Rajashekhar Gangaraju
Diabetic retinopathy (DR) is the leading cause of vision loss among working-age adults. The interplay between hyperglycemia and endothelial activation in inducing endoplasmic reticulum (ER) stress pathways and visual deficits in DR is not fully understood. To address this, we used a mouse model of chronic vascular activation using endothelial-specific tumor necrosis factor-α (TNF-α)-expressing (tie2-TNF) mice to induce diabetes with streptozotocin. At 4 weeks post streptozotocin, a significant 2-fold to 10-fold increase in retinal neurovascular inflammatory gene transcript response in tie2-TNF mice was further increased in diabetic tie2-TNF mice...
July 27, 2018: Journal of Cellular Biochemistry
Mohammed N A Siddiquey, Hongbo Zhang, Christopher C Nguyen, Anthony J Domma, Jeremy P Kamil
Eukaryotic cells are equipped with three sensors that respond to the accumulation of misfolded proteins within the lumen of the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR), which functions to resolve proteotoxic stresses involving the secretory pathway. Here, we identify UL148, a viral ER resident glycoprotein from human cytomegalovirus (HCMV), as an inducer of the UPR. Metabolic labeling results indicate that global mRNA translation is decreased when UL148 expression is induced in uninfected cells...
July 25, 2018: Journal of Virology
Gulsah Albayrak, Ece Konac, Asiye Ugras Dikmen, Cenk Y Bilen
Prostate cancer is one of the most common types of cancer in men and the leading cause of death in developed countries. With the aid of molecular and genetic profiling of cancers, cancer molecular subtypes are paving the way for tailored cancer therapy. FOXA1 has been identified as one of the seven molecular subtypes of prostate cancer. FOXA1 is involved in a variety of metabolic process such as glucose homeostasis and deregulation of its expression is crucial in prostate cancer progression. In this study, we investigated the effects of FOXA1 gene knock-out on the expression levels of various cancer cell metabolism and cell cycle-related protein expressions...
July 25, 2018: Experimental Biology and Medicine
Aitor Almanza, Antonio Carlesso, Chetan Chintha, Stuart Creedican, Dimitrios Doultsinos, Brian Leuzzi, Andreia Luís, Nicole McCarthy, Luigi Montibeller, Sanket More, Alexandra Papaioannou, Franziska Püschel, Maria Livia Sassano, Josip Skoko, Patrizia Agostinis, Jackie de Belleroche, Leif A Eriksson, Simone Fulda, Adrienne M Gorman, Sandra Healy, Andrey Kozlov, Cristina Muñoz-Pinedo, Markus Rehm, Eric Chevet, Afshin Samali
The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions...
July 20, 2018: FEBS Journal
Bingyu Ren, Yujuan Wang, Heng Wang, Yingying Wu, Jiayi Li, Jing Tian
Severity or duration of endoplasmic reticulum (ER) stress leads to two different cellular events: cell survival and apoptosis. Drug-induced ER stress or neurotoxicity has been observed as one of the main side effects. However, how ER stress affects cellular signaling cascades leading to neuronal damage is still not well understood. In this study, the toxicological mechanisms of two typical ER stress inducers, tunicamycin (Tm) and dithiothreitol (DTT), were investigated by cell viability, unfolded protein response, apoptosis and proteomic responses in mouse neuro-2a cells...
July 10, 2018: Neurotoxicology
Zhaoqianqi Feng, Huaimin Wang, Shiyu Wang, Qiang Zhang, Xixiang Zhang, Avital A Rodal, Bing Xu
The endoplasmic reticulum (ER) is responsible for the synthesis and folding of a large number of proteins, as well as intracellular calcium regulation, lipid synthesis, and lipid transfer to other organelles, and is emerging as a target for cancer therapy. However, strategies for selectively targeting the ER of cancer cells are limited. Here we show that enzymatically generated crescent-shaped supramolecular assemblies of short peptides disrupt cell membranes and target ER for selective cancer cell death. As revealed by sedimentation assay, the assemblies interact with synthetic lipid membranes...
August 1, 2018: Journal of the American Chemical Society
S Pignani, A Todaro, M Ferrarese, S Marchi, S Lombardi, D Balestra, P Pinton, F Bernardi, M Pinotti, A Branchini
BACKGROUND: Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone-like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. OBJECTIVES: To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I Haemophilia B (HB) through chaperone-like compounds...
July 11, 2018: Journal of Thrombosis and Haemostasis: JTH
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