Biochemical and Cellular Mechanisms Regulating ER-to-Golgi Vesicular Trafficking in Health and Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 16899

Special Issue Editors

Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvador Allende, 84081 Baronissi, Italy
Interests: vesicular trafficking; unfolded protein response; endoplasmic reticulum stress; ER mitochondria interplay; neurodegenerative disorders; cancer
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy
Interests: control of protein homeostasis in health and disease and therapeutic approaches
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy
Interests: membrane trafficking; endoplasmic reticulum stress; unfolded protein response; oxidative stress; mitochondrial dysfunction; mitochondrial associated membranes (MAMs); parkinson's disease; phosphoinositides function

Special Issue Information

Dear Colleagues,

Secretory proteins and membranes exit the ER into ER-derived carriers and are transported to the Golgi before being sorted and delivered to their final destinations. This task is fundamental for the maintenance and function of secretory pathway compartments as well as for extracellular environment roles.  The Unfolded Protein Response pathways, which preside over the control of proteostasis within the secretory pathway, the assembly of the multiprotein complex COPII at the ER membranes, and the ER-phagy are principal actors in ER-to-Golgi trafficking control.  In this Special Issue, we welcome scientific contributions that describe novel cellular mechanisms and their interconnections implicated in ER-to-Golgi trafficking control and that discuss how defects of the molecular machinery that control ER-export result in diverse human diseases. We also welcome scientific reports that show and/or discuss possible therapeutic approaches that may be used in the treatment of ER-to Golgi trafficking-based disorders.

Dr. Paolo Remondelli
Dr. Ornella Moltedo
Dr. Giuseppina Amodio
Guest Editors

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Keywords

  • ER-to-Golgi trafficking
  • UPR pathways
  • COPII
  • ER-phagy
  • secretory pathway proteostasis
  • cancer
  • neurodegenerative disorders

Published Papers (7 papers)

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Research

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21 pages, 12799 KiB  
Article
Myogenesis in C2C12 Cells Requires Phosphorylation of ATF6α by p38 MAPK
by Valentina Pagliara, Giuseppina Amodio, Vincenzo Vestuto, Silvia Franceschelli, Nicola Antonino Russo, Vittorio Cirillo, Giovanna Mottola, Paolo Remondelli and Ornella Moltedo
Biomedicines 2023, 11(5), 1457; https://doi.org/10.3390/biomedicines11051457 - 16 May 2023
Viewed by 1969
Abstract
Activating transcription factor 6α (ATF6α) is an endoplasmic reticulum protein known to participate in unfolded protein response (UPR) during ER stress in mammals. Herein, we show that in mouse C2C12 myoblasts induced to differentiate, ATF6α is the only pathway of the UPR activated. [...] Read more.
Activating transcription factor 6α (ATF6α) is an endoplasmic reticulum protein known to participate in unfolded protein response (UPR) during ER stress in mammals. Herein, we show that in mouse C2C12 myoblasts induced to differentiate, ATF6α is the only pathway of the UPR activated. ATF6α stimulation is p38 MAPK-dependent, as revealed by the use of the inhibitor SB203580, which halts myotube formation and, at the same time, impairs trafficking of ATF6α, which accumulates at the cis-Golgi without being processed in the p50 transcriptional active form. To further evaluate the role of ATF6α, we knocked out the ATF6α gene, thus inhibiting the C2C12 myoblast from undergoing myogenesis, and this occurred independently from p38 MAPK activity. The expression of exogenous ATF6α in knocked-out ATF6α cells recover myogenesis, whereas the expression of an ATF6α mutant in the p38 MAPK phosphorylation site (T166) was not able to regain myogenesis. Genetic ablation of ATF6α also prevents the exit from the cell cycle, which is essential for muscle differentiation. Furthermore, when we inhibited differentiation by the use of dexamethasone in C2C12 cells, we found inactivation of p38 MAPK and, consequently, loss of ATF6α activity. All these findings suggest that the p-p38 MAPK/ATF6α axis, in pathophysiological conditions, regulates myogenesis by promoting the exit from the cell cycle, an essential step to start myoblasts differentiation. Full article
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22 pages, 7108 KiB  
Article
Impact of Hypermannosylation on the Structure and Functionality of the ER and the Golgi Complex
by Patricia Franzka, Svenja Caren Schüler, Takfarinas Kentache, Robert Storm, Andrea Bock, Istvan Katona, Joachim Weis, Katrin Buder, Christoph Kaether and Christian A. Hübner
Biomedicines 2023, 11(1), 146; https://doi.org/10.3390/biomedicines11010146 - 06 Jan 2023
Viewed by 1726
Abstract
Proteins of the secretory pathway undergo glycosylation in the endoplasmic reticulum (ER) and the Golgi apparatus. Altered protein glycosylation can manifest in serious, sometimes fatal malfunctions. We recently showed that mutations in GDP-mannose pyrophosphorylase A (GMPPA) can cause a syndrome characterized by alacrima, [...] Read more.
Proteins of the secretory pathway undergo glycosylation in the endoplasmic reticulum (ER) and the Golgi apparatus. Altered protein glycosylation can manifest in serious, sometimes fatal malfunctions. We recently showed that mutations in GDP-mannose pyrophosphorylase A (GMPPA) can cause a syndrome characterized by alacrima, achalasia, mental retardation, and myopathic alterations (AAMR syndrome). GMPPA acts as a feedback inhibitor of GDP-mannose pyrophosphorylase B (GMPPB), which provides GDP-mannose as a substrate for protein glycosylation. Loss of GMPPA thus enhances the incorporation of mannose into glycochains of various proteins, including α-dystroglycan (α-DG), a protein that links the extracellular matrix with the cytoskeleton. Here, we further characterized the consequences of loss of GMPPA for the secretory pathway. This includes a fragmentation of the Golgi apparatus, which comes along with a regulation of the abundance of several ER- and Golgi-resident proteins. We further show that the activity of the Golgi-associated endoprotease furin is reduced. Moreover, the fraction of α-DG, which is retained in the ER, is increased. Notably, WT cells cultured at a high mannose concentration display similar changes with increased retention of α-DG, altered structure of the Golgi apparatus, and a decrease in furin activity. In summary, our data underline the importance of a balanced mannose homeostasis for the secretory pathway. Full article
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19 pages, 6816 KiB  
Article
Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK
by Vincenzo Vestuto, Giuseppina Amodio, Giacomo Pepe, Manuela Giovanna Basilicata, Raffaella Belvedere, Enza Napolitano, Daniela Guarnieri, Valentina Pagliara, Simona Paladino, Manuela Rodriquez, Alessia Bertamino, Pietro Campiglia, Paolo Remondelli and Ornella Moltedo
Biomedicines 2022, 10(8), 2009; https://doi.org/10.3390/biomedicines10082009 - 18 Aug 2022
Cited by 9 | Viewed by 2547
Abstract
Parkinson’s disease (PD) represents one of the most common neurodegenerative disorders, characterized by a dopamine (DA) deficiency in striatal synapses and misfolded toxic α-synuclein aggregates with concomitant cytotoxicity. In this regard, the misfolded proteins accumulation in neurodegenerative disorders induces a remarkable perturbations of [...] Read more.
Parkinson’s disease (PD) represents one of the most common neurodegenerative disorders, characterized by a dopamine (DA) deficiency in striatal synapses and misfolded toxic α-synuclein aggregates with concomitant cytotoxicity. In this regard, the misfolded proteins accumulation in neurodegenerative disorders induces a remarkable perturbations of endoplasmic reticulum (ER) homeostasis leading to persistent ER stress, which in turn, effects protein synthesis, modification, and folding quality control. A large body of evidence suggests that natural products target the ER stress signaling pathway, exerting a potential action in cancers, diabetes, cardiovascular and neurodegenerative diseases. This study aims to assess the neuroprotective effect of cocoa extract and its purified fractions against a cellular model of Parkinson’s disease represented by 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma. Our findings demonstrate, for the first time, the ability of cocoa to specifically targets PERK sensor, with significant antioxidant and antiapoptotic activities as both crude and fractioning extracts. In addition, cocoa also showed antiapoptotic properties in 3D cell model and a notable ability to inhibit the accumulation of α-synuclein in 6-OHDA-induced cells. Overall, these results indicate that cocoa exerts neuroprotective effects suggesting a novel possible strategy to prevent or, at least, mitigate neurodegenerative disorders, such as PD. Full article
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22 pages, 7460 KiB  
Article
Oxidative Stress-Induced Growth Inhibitor (OSGIN1), a Target of X-Box-Binding Protein 1, Protects Palmitic Acid-Induced Vascular Lipotoxicity through Maintaining Autophagy
by Chong-Sun Khoi, Cai-Qin Xiao, Kuan-Yu Hung, Tzu-Yu Lin and Chih-Kang Chiang
Biomedicines 2022, 10(5), 992; https://doi.org/10.3390/biomedicines10050992 - 25 Apr 2022
Cited by 4 | Viewed by 2311
Abstract
Saturated free fatty acids (FFAs) strongly correlate with metabolic syndromes and are well-known risk factors for cardiovascular diseases (CVDs). The mechanism of palmitic acid (PA)-induced vascular lipotoxicity under endoplasmic reticulum (ER) stress is unknown. In the present paper, we investigate the roles of [...] Read more.
Saturated free fatty acids (FFAs) strongly correlate with metabolic syndromes and are well-known risk factors for cardiovascular diseases (CVDs). The mechanism of palmitic acid (PA)-induced vascular lipotoxicity under endoplasmic reticulum (ER) stress is unknown. In the present paper, we investigate the roles of spliced form of X-box-binding protein 1 (XBP1s) target gene oxidative stress-induced growth inhibitor 1 (OSGIN1) in PA-induced vascular dysfunction. PA inhibited the tube formation assay of primary human umbilical vein endothelial cells (HUVECs). Simultaneously, PA treatment induced the XBP1s expression in HUVECs. Attenuate the induction of XBP1s by silencing the XBP1s retarded cell migration and diminished endothelial nitric oxide synthase (eNOS) expression. OSGIN1 is a target gene of XBP1s under PA treatment. The silencing of OSGIN1 inhibits cell migration by decreasing phospho-eNOS expression. PA activated autophagy in endothelial cells, inhibiting autophagy by 3-methyladenine (3-MA) decreased endothelial cell migration. Silencing XBP1s and OSGIN1 would reduce the induction of LC3 II; therefore, OSGIN1 could maintain autophagy to preserve endothelial cell migration. In conclusion, PA treatment induced ER stress and activated the inositol-requiring enzyme 1 alpha–spliced XBP1 (IRE1α–XBP1s) pathway. OSGIN1, a target gene of XBP1s, could protect endothelial cells from vascular lipotoxicity by regulating autophagy. Full article
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15 pages, 4111 KiB  
Article
Differential Expression and Localization of EHBP1L1 during the First Wave of Rat Spermatogenesis Suggest Its Involvement in Acrosome Biogenesis
by Massimo Venditti and Sergio Minucci
Biomedicines 2022, 10(1), 181; https://doi.org/10.3390/biomedicines10010181 - 16 Jan 2022
Cited by 8 | Viewed by 1880
Abstract
The identification and characterization of new proteins involved in spermatogenesis is fundamental, considering that good-quality gametes are basic in ensuring proper reproduction. Here, we further analyzed the temporal and spatial localization during the first spermatogenic wave of rat testis of EHBP1L1, which is [...] Read more.
The identification and characterization of new proteins involved in spermatogenesis is fundamental, considering that good-quality gametes are basic in ensuring proper reproduction. Here, we further analyzed the temporal and spatial localization during the first spermatogenic wave of rat testis of EHBP1L1, which is involved in vesicular trafficking due to the CH and bMERB domains, which bind to actin and Rab8/10, respectively. Western blot and immunofluorescence analyses showed that EHBP1L1 protein expression started at 21 days post-partum (dpp) concomitantly with the appearance of primary spermatocytes (I SPC). In subsequent stages, EHBP1L1 specifically localized together with actin in the perinuclear cytoplasm close to the acrosomal and Golgian regions of spermatids (SPT) during the different phases of acrosome biogenesis (AB). Moreover, it was completely absent in elongated SPT and in mature spermatozoa, suggesting that its role was completed in previous stages. The combined data, also supported by our previous report demonstrating that EHBP1L1 mRNA was expressed by primary (I) and secondary (II) SPC, lead us to hypothesize its specific role during AB. Although these results are suggestive, further studies are needed to better clarify the underlying molecular mechanisms of AB, with the aim to use EHBP1L1 as a potential new marker for spermatogenesis. Full article
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Review

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17 pages, 1088 KiB  
Review
The Unfolded Protein Response and Its Implications for Novel Therapeutic Strategies in Inflammatory Bowel Disease
by Noel Verjan Garcia, Kyung U. Hong and Nobuyuki Matoba
Biomedicines 2023, 11(7), 2066; https://doi.org/10.3390/biomedicines11072066 - 23 Jul 2023
Cited by 2 | Viewed by 1669
Abstract
The endoplasmic reticulum (ER) is a multifunctional organelle playing a vital role in maintaining cell homeostasis, and disruptions to its functions can have detrimental effects on cells. Dysregulated ER stress and the unfolded protein response (UPR) have been linked to various human diseases. [...] Read more.
The endoplasmic reticulum (ER) is a multifunctional organelle playing a vital role in maintaining cell homeostasis, and disruptions to its functions can have detrimental effects on cells. Dysregulated ER stress and the unfolded protein response (UPR) have been linked to various human diseases. For example, ER stress and the activation of the UPR signaling pathways in intestinal epithelial cells can either exacerbate or alleviate the severity of inflammatory bowel disease (IBD), contingent on the degree and conditions of activation. Our recent studies have shown that EPICERTIN, a recombinant variant of the cholera toxin B subunit containing an ER retention motif, can induce a protective UPR in colon epithelial cells, subsequently promoting epithelial restitution and mucosal healing in IBD models. These findings support the idea that compounds modulating UPR may be promising pharmaceutical candidates for the treatment of the disease. In this review, we summarize our current understanding of the ER stress and UPR in IBD, focusing on their roles in maintaining cell homeostasis, dysregulation, and disease pathogenesis. Additionally, we discuss therapeutic strategies that promote the cytoprotection of colon epithelial cells and reduce inflammation via pharmacological manipulation of the UPR. Full article
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16 pages, 2760 KiB  
Review
KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities
by Ilaria Cela, Beatrice Dufrusine, Claudia Rossi, Alberto Luini, Vincenzo De Laurenzi, Luca Federici and Michele Sallese
Biomedicines 2022, 10(6), 1234; https://doi.org/10.3390/biomedicines10061234 - 25 May 2022
Cited by 6 | Viewed by 3573
Abstract
KDEL receptors (KDELRs) are ubiquitous seven-transmembrane domain proteins encoded by three mammalian genes. They bind to and retro-transport endoplasmic reticulum (ER)-resident proteins with a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence or variants thereof. In doing this, KDELR participates in the ER quality control of newly [...] Read more.
KDEL receptors (KDELRs) are ubiquitous seven-transmembrane domain proteins encoded by three mammalian genes. They bind to and retro-transport endoplasmic reticulum (ER)-resident proteins with a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence or variants thereof. In doing this, KDELR participates in the ER quality control of newly synthesized proteins and the unfolded protein response. The binding of KDEL proteins to KDELR initiates signaling cascades involving three alpha subunits of heterotrimeric G proteins, Src family kinases, protein kinases A (PKAs), and mitogen-activated protein kinases (MAPKs). These signaling pathways coordinate membrane trafficking flows between secretory compartments and control the degradation of the extracellular matrix (ECM), an important step in cancer progression. Considering the basic cellular functions performed by KDELRs, their association with various diseases is not surprising. KDELR mutants unable to bind the collagen-specific chaperon heat-shock protein 47 (HSP47) cause the osteogenesis imperfecta. Moreover, the overexpression of KDELRs appears to be linked to neurodegenerative diseases that share pathological ER-stress and activation of the unfolded protein response (UPR). Even immune function requires a functional KDELR1, as its mutants reduce the number of T lymphocytes and impair antiviral immunity. Several studies have also brought to light the exploitation of the shuttle activity of KDELR during the intoxication and maturation/exit of viral particles. Based on the above, KDELRs can be considered potential targets for the development of novel therapeutic strategies for a variety of diseases involving proteostasis disruption, cancer progression, and infectious disease. However, no drugs targeting KDELR functions are available to date; rather, KDELR has been leveraged to deliver drugs efficiently into cells or improve antigen presentation. Full article
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