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Golgi Stress Response: New Insights into the Pathogenesis and Therapeutic Targets of Human Diseases.Molecules and Cells Apr 2023The Golgi apparatus modifies and transports secretory and membrane proteins. In some instances, the production of secretory and membrane proteins exceeds the capacity of... (Review)
Review
The Golgi apparatus modifies and transports secretory and membrane proteins. In some instances, the production of secretory and membrane proteins exceeds the capacity of the Golgi apparatus, including vesicle trafficking and the post-translational modification of macromolecules. These proteins are not modified or delivered appropriately due to insufficiency in the Golgi function. These conditions disturb Golgi homeostasis and induce a cellular condition known as Golgi stress, causing cells to activate the 'Golgi stress response,' which is a homeostatic process to increase the capacity of the Golgi based on cellular requirements. Since the Golgi functions are diverse, several response pathways involving TFE3, HSP47, CREB3, proteoglycan, mucin, MAPK/ETS, and PERK regulate the capacity of each Golgi function separately. Understanding the Golgi stress response is crucial for revealing the mechanisms underlying Golgi dynamics and its effect on human health because many signaling molecules are related to diseases, ranging from viral infections to fatal neurodegenerative diseases. Therefore, it is valuable to summarize and investigate the mechanisms underlying Golgi stress response in disease pathogenesis, as they may contribute to developing novel therapeutic strategies. In this review, we investigate the perturbations and stress signaling of the Golgi, as well as the therapeutic potentials of new strategies for treating Golgi stress-associated diseases.
Topics: Humans; Golgi Apparatus; Protein Processing, Post-Translational; Protein Transport; Signal Transduction; Membrane Proteins
PubMed: 36574967
DOI: 10.14348/molcells.2023.2152 -
Cells Feb 2020Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to... (Review)
Review
Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans.
Topics: Endoplasmic Reticulum; Golgi Apparatus; Humans; Nervous System Diseases; Protein Transport; Proteins
PubMed: 32053905
DOI: 10.3390/cells9020408 -
Trends in Cell Biology Jun 2020The Golgi apparatus serves as a receiving station where proteins from the endoplasmic reticulum (ER) are further processed before being sent to other cellular... (Review)
Review
The Golgi apparatus serves as a receiving station where proteins from the endoplasmic reticulum (ER) are further processed before being sent to other cellular compartments. In addition to its well-appreciated roles in vesicular trafficking and protein/lipid secretion, recent studies have demonstrated that the Golgi acts as a signaling platform to facilitate multiple innate immune pathways. Moreover, the membranous networks that connect the Golgi with the ER, mitochondria, endosomes, and autophagosomes provide convenient access to innate immune signal transduction and subsequent effector responses. Here, we review the emerging knowledge about the roles of the Golgi in the initiation and activation of innate immune signaling. Moreover, microbial hijacking strategies that inhibit Golgi-associated innate immune responses will also be discussed.
Topics: Animals; Bacteria; Golgi Apparatus; Humans; Immunity, Innate; Inflammasomes; Models, Biological
PubMed: 32413316
DOI: 10.1016/j.tcb.2020.02.008 -
ACS Nano Nov 2023Innate and adaptive immunity is important for initiating and maintaining immune function. The nucleotide-binding oligomerization domain-like receptor family pyrin...
Innate and adaptive immunity is important for initiating and maintaining immune function. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves as a checkpoint in innate and adaptive immunity, promoting the secretion of pro-inflammatory cytokines and gasdermin D-mediated pyroptosis. As a highly inflammatory form of cell death distinct from apoptosis, pyroptosis can trigger immunogenic cell death and promote systemic immune responses in solid tumors. Previous studies proposed that NLRP3 was activated by translocation to the mitochondria. However, a recent authoritative study has challenged this model and proved that the Golgi apparatus might be a prerequisite for the activation of NLRP3. In this study, we first developed a Golgi apparatus-targeted photodynamic strategy to induce the activation of NLRP3 by precisely locating organelles. We found that Golgi apparatus-targeted photodynamic therapy could significantly upregulate NLRP3 expression to promote the subsequent release of intracellular proinflammatory contents such as IL-1β or IL-18, creating an inflammatory storm to enhance innate immunity. Moreover, this acute NLRP3 upregulation also activated its downstream classical caspase-1-dependent pyroptosis to enhance tumor immunogenicity, triggering adaptive immunity. Pyroptosis eventually led to immunogenic cell death, promoted the maturation of dendritic cells, and effectively activated antitumor immunity and long-lived immune memory. Overall, this Golgi apparatus-targeted strategy provided molecular insights into the occurrence of immunogenic pyroptosis and offered a platform to remodel the tumor microenvironment.
Topics: NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Inflammasomes; Immunity, Innate; Golgi Apparatus; Interleukin-1beta; Caspase 1
PubMed: 37921421
DOI: 10.1021/acsnano.3c05005 -
Proceedings of the National Academy of... May 2023The Golgi is a membrane-bound organelle that is essential for protein and lipid biosynthesis. It represents a central trafficking hub that sorts proteins and lipids to...
The Golgi is a membrane-bound organelle that is essential for protein and lipid biosynthesis. It represents a central trafficking hub that sorts proteins and lipids to various destinations or for secretion from the cell. The Golgi has emerged as a docking platform for cellular signaling pathways including LRRK2 kinase whose deregulation leads to Parkinson disease. Golgi dysfunction is associated with a broad spectrum of diseases including cancer, neurodegeneration, and cardiovascular diseases. To allow the study of the Golgi at high resolution, we report a rapid Golgi immunoprecipitation technique (Golgi-IP) to isolate intact Golgi mini-stacks for subsequent analysis of their content. By fusing the Golgi-resident protein TMEM115 to three tandem HA epitopes (GolgiTAG), we purified the Golgi using Golgi-IP with minimal contamination from other compartments. We then established an analysis pipeline using liquid chromatography coupled with mass spectrometry to characterize the human Golgi proteome, metabolome, and lipidome. Subcellular proteomics confirmed known Golgi proteins and identified proteins not previously associated with the Golgi. Metabolite profiling established the human Golgi metabolome and revealed the enrichment of uridine-diphosphate (UDP) sugars and their derivatives, which is consistent with their roles in protein and lipid glycosylation. Furthermore, targeted metabolomics validated SLC35A2 as the subcellular transporter for UDP-hexose. Finally, lipidomics analysis showed that phospholipids including phosphatidylcholine, phosphatidylinositol, and phosphatidylserine are the most abundant Golgi lipids and that glycosphingolipids are enriched in this compartment. Altogether, our work establishes a comprehensive molecular map of the human Golgi and provides a powerful method to study the Golgi with high precision in health and disease.
Topics: Humans; Golgi Apparatus; Chromatography, Liquid; Proteome; Lipids; Uridine Diphosphate
PubMed: 37155866
DOI: 10.1073/pnas.2219953120 -
Journal of Cell Science Aug 2019A hallmark of eukaryotic cells is the spatial separation of molecular and biochemical processes into membrane-bound organelles, such as mitochondria, endoplasmic... (Review)
Review
A hallmark of eukaryotic cells is the spatial separation of molecular and biochemical processes into membrane-bound organelles, such as mitochondria, endoplasmic reticulum and Golgi. At the 'Cell dynamics: organelle-cytoskeleton interface' meeting held in Lisbon, researchers from around the world discussed their findings of how the cytoskeleton regulates dynamics, interaction, and function of organelles in health and disease. Organised by Edgar Gomes, Heidi McBride, Sharon Tooze and Michael Way, the meeting created an open, stimulating and collaborative environment for scientific exchange and an opportunity to highlight the newest trends in the field.
Topics: Animals; Congresses as Topic; Cytoskeleton; Endoplasmic Reticulum; Golgi Apparatus; Humans; Mitochondria
PubMed: 31416851
DOI: 10.1242/jcs.236679 -
Cell Biology International Sep 2022The Golgi apparatus is a membrane-bound organelle that functions as a central role in the secretory pathway. Since the discovery of the Golgi apparatus, its structure... (Review)
Review
The Golgi apparatus is a membrane-bound organelle that functions as a central role in the secretory pathway. Since the discovery of the Golgi apparatus, its structure and function have attracted ever-increasing attention from researchers. Recently, it has been demonstrated that metal ions are necessary for the Golgi apparatus to maintain its proper structure and functions. Given that metal ions play an important role in various biological processes, their abnormal homeostasis is related to many diseases. Therefore, in this paper, we reviewed the uptake and release mechanisms of the Golgi apparatus Ca , Cu, and Zn . Furthermore, we describe the diseases associated with Golgi apparatus Ca , Cu, and Zn imbalance.
Topics: Biological Transport; Calcium; Golgi Apparatus; Ions
PubMed: 35830695
DOI: 10.1002/cbin.11848 -
Non-canonical Golgi-compartmentalized Gβγ signaling: mechanisms, functions, and therapeutic targets.Trends in Pharmacological Sciences Feb 2023G protein Gβγ subunits are key mediators of G protein-coupled receptor (GPCR) signaling under physiological and pathological conditions; their inhibitors have been... (Review)
Review
G protein Gβγ subunits are key mediators of G protein-coupled receptor (GPCR) signaling under physiological and pathological conditions; their inhibitors have been tested for the treatment of human disease. Conventional wisdom is that the Gβγ complex is activated and subsequently exerts its functions at the plasma membrane (PM). Recent studies have revealed non-canonical activation of Gβγ at intracellular organelles, where the Golgi apparatus is a major locale, via translocation or local activation. Golgi-localized Gβγ activates specific signaling cascades and regulates fundamental cell processes such as membrane trafficking, proliferation, and migration. More recent studies have shown that inhibiting Golgi-compartmentalized Gβγ signaling attenuates cardiomyocyte hypertrophy and prostate tumorigenesis, indicating new therapeutic targets. We review novel activation mechanisms and non-canonical functions of Gβγ at the Golgi, and discuss potential therapeutic interventions by targeting Golgi-biased Gβγ-directed signaling.
Topics: Humans; GTP-Binding Protein beta Subunits; GTP-Binding Protein gamma Subunits; Signal Transduction; Golgi Apparatus; Cell Membrane
PubMed: 36494204
DOI: 10.1016/j.tips.2022.11.003 -
Science Signaling Mar 2024Activation of the endoplasmic reticulum (ER)-resident adaptor protein STING, a component of a cytosolic DNA-sensing pathway, induces the transcription of genes encoding...
Activation of the endoplasmic reticulum (ER)-resident adaptor protein STING, a component of a cytosolic DNA-sensing pathway, induces the transcription of genes encoding type I interferons (IFNs) and other proinflammatory factors. Because STING is activated at the Golgi apparatus, control of the localization and activation of STING is important in stimulating antiviral and antitumor immune responses. Through a genome-wide CRISPR interference screen, we found that STING activation required the Golgi-resident protein ACBD3, which promotes the generation of phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi network, as well as other PI4P-associated proteins. Appropriate localization and activation of STING at the Golgi apparatus required ACBD3 and the PI4P-generating kinase PI4KB. In contrast, STING activation was enhanced when the lipid-shuttling protein OSBP, which removes PI4P from the Golgi apparatus, was inhibited by the US Food and Drug Administration-approved antifungal itraconazole. The increase in the abundance of STING-activating phospholipids at the trans-Golgi network resulted in the increased production of IFN-β and other cytokines in THP-1 cells. Furthermore, a mutant STING that could not bind to PI4P failed to traffic from the ER to the Golgi apparatus in response to a STING agonist, whereas forced relocalization of STING to PI4P-enriched areas elicited STING activation in the absence of stimulation with a STING agonist. Thus, PI4P is critical for STING activation, and manipulating PI4P abundance may therapeutically modulate STING-dependent immune responses.
Topics: Phospholipids; Golgi Apparatus; Adaptor Proteins, Signal Transducing
PubMed: 38470955
DOI: 10.1126/scisignal.ade3643 -
International Journal of Biological... Jan 2022The Golgi complex is an essential organelle of the eukaryotic exocytic pathway. A subfamily of Golgi matrix proteins, called GRASPs, is central in stress-induced...
The Golgi complex is an essential organelle of the eukaryotic exocytic pathway. A subfamily of Golgi matrix proteins, called GRASPs, is central in stress-induced unconventional secretion, Golgi dynamics during mitosis/apoptosis, and Golgi ribbon formation. The Golgi ribbon is vertebrate-specific and correlates with the appearance of two GRASP paralogues and two Golgins (GM130/Golgin45), which form specific GRASP-Golgin pairs. The molecular details of their appearance only in Metazoans are unknown. Moreover, despite new functionalities supported by GRASP paralogy, little is known about their structural and evolutionary differences. Here, we used ancestor sequence reconstruction and biophysical/biochemical approaches to assess the evolution of GRASPs structure/dynamics, fibrillation, and how they started anchoring their Golgin partners. Our data showed that a GRASP ancestor anchored Golgins before gorasp gene duplication in Metazoans. After gene duplication, variations within the GRASP binding pocket determined which paralogue would recruit which Golgin. These interactions are responsible for their specific Golgi location and Golgi ribbon appearance. We also suggest that GRASPs have a long-standing capacity to form supramolecular structures, affecting their participation in stress-induced processes.
Topics: Amino Acid Sequence; Golgi Apparatus; Golgi Matrix Proteins; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Phylogeny; Protein Binding; Protein Conformation; Protein Transport; Stress, Physiological; Structure-Activity Relationship; Thermodynamics
PubMed: 34861272
DOI: 10.1016/j.ijbiomac.2021.11.173