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Biology of the Cell Mar 2021Cell biology is evolving to become a more formal and quantitative science. In particular, several mathematical models have been proposed to address Golgi... (Review)
Review
BACKGROUND
Cell biology is evolving to become a more formal and quantitative science. In particular, several mathematical models have been proposed to address Golgi self-organisation and protein and lipid transport. However, most scientific articles about the Golgi apparatus are still using static cartoons that miss the dynamism of this organelle.
RESULTS
In this report, we show that schematic drawings of Golgi trafficking can be easily translated into an agent-based model using the Repast platform. The simulations generate an active interplay among cisternae and vesicles rendering quantitative predictions about Golgi stability and transport of soluble and membrane-associated cargoes. The models can incorporate complex networks of molecular interactions and chemical reactions by association with COPASI, a software that handles ordinary differential equations.
CONCLUSIONS
The strategy described provides a simple, flexible and multiscale support to analyse Golgi transport. The simulations can be used to address issues directly linked to the mechanism of transport or as a way to incorporate the complexity of trafficking to other cellular processes that occur in dynamic organelles.
SIGNIFICANCE
We show that the rules implicitly present in most schematic representations of intracellular trafficking can be used to build dynamic models with quantitative outputs that can be compared with experimental results.
Topics: Biological Transport; Golgi Apparatus; Humans
PubMed: 33275796
DOI: 10.1111/boc.202000107 -
Small GTPases Dec 2023Next year marks one-quarter of a century since the discovery of the so-called COPI-independent pathway, which operates between the Golgi apparatus and the endoplasmic... (Review)
Review
Next year marks one-quarter of a century since the discovery of the so-called COPI-independent pathway, which operates between the Golgi apparatus and the endoplasmic reticulum (ER) in eukaryotic cells. Unlike almost all other intracellular trafficking pathways, this pathway is not regulated by the physical accumulation of multisubunit proteinaceous coat molecules, but instead by the small GTPase Rab6. What also sets it apart from other pathways is that the transport carriers themselves often take the form of tubules, rather than conventional vesicles. In this review, we assess the relevant literature that has accumulated to date, in an attempt to provide a concerted description of how this pathway is regulated. We discuss the possible cargo molecules that are carried in this pathway, and the likely mechanism of Rab6 tubule biogenesis, including how the cargo itself may play a critical role. We also provide perspective surrounding the various molecular motors of the kinesin, myosin and dynein families that have been implicated in driving Rab6-coated tubular membranes long distances through the cell prior to delivering their cargo to the ER. Finally, we also raise several important questions that require resolution, if we are to ultimately provide a comprehensive molecular description of how the COPI-independent pathway is controlled.
Topics: Humans; HeLa Cells; Golgi Apparatus; Endoplasmic Reticulum; Coat Protein Complex I; Protein Transport
PubMed: 37488775
DOI: 10.1080/21541248.2023.2238330 -
Bioscience Reports May 2022Lysosomes are key regulators of many fundamental cellular processes such as metabolism, autophagy, immune response, cell signalling and plasma membrane repair. These... (Review)
Review
Lysosomes are key regulators of many fundamental cellular processes such as metabolism, autophagy, immune response, cell signalling and plasma membrane repair. These highly dynamic organelles are composed of various membrane and soluble proteins, which are essential for their proper functioning. The soluble proteins include numerous proteases, glycosidases and other hydrolases, along with activators, required for catabolism. The correct sorting of soluble lysosomal proteins is crucial to ensure the proper functioning of lysosomes and is achieved through the coordinated effort of many sorting receptors, resident ER and Golgi proteins, and several cytosolic components. Mutations in a number of proteins involved in sorting soluble proteins to lysosomes result in human disease. These can range from rare diseases such as lysosome storage disorders, to more prevalent ones, such as Alzheimer's disease, Parkinson's disease and others, including rare neurodegenerative diseases that affect children. In this review, we discuss the mechanisms that regulate the sorting of soluble proteins to lysosomes and highlight the effects of mutations in this pathway that cause human disease. More precisely, we will review the route taken by soluble lysosomal proteins from their translation into the ER, their maturation along the Golgi apparatus, and sorting at the trans-Golgi network. We will also highlight the effects of mutations in this pathway that cause human disease.
Topics: Child; Golgi Apparatus; Humans; Lysosomes; Protein Transport; Proteins
PubMed: 35394021
DOI: 10.1042/BSR20211856 -
Journal of Environmental Pathology,... 2020Among the neurodegenerative diseases, Alzheimer's disease (AD) is a predominant public health issue, affecting 16 million people around the world. It is clinically... (Review)
Review
Among the neurodegenerative diseases, Alzheimer's disease (AD) is a predominant public health issue, affecting 16 million people around the world. It is clinically manifested by the presence of amyloid plaques (Aβ) and neurofibrillary tangles (NFT) within the brain. Due to intraneuronal processing, Aβ interacts with cellular targets such as mitochondria, ER, and Golgi apparatus and hampers their normal functions. Alteration in the mitochondrial function, closely related to the production of reactive oxygen species (ROS), Ca+2 overload, and apoptosis in the brain, is one of the key pathological events studied in AD pathogenesis. It is also an important pivot for the intracellular interaction with ER and Golgi through signal transduction and membrane contact to regulate cell survival and death mechanism. Alteration in mitochondrial function is intimately connected with abnormal ER or Golgi function. Stimuli that enhance perturbation in the normal ER or Golgi organelles function can involve mitochondria mediated apoptotic cell death. In this review, we address the importance of the mitochondria and their cross talk with ER and Golgi in AD pathogenesis and animal models with a therapeutic strategy to improve the mitochondrial functions.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apoptosis; Brain; Endoplasmic Reticulum; Golgi Apparatus; Humans; Mitochondria; Signal Transduction
PubMed: 32865917
DOI: 10.1615/JEnvironPatholToxicolOncol.2020034249 -
Traffic (Copenhagen, Denmark) Aug 2023Deficiency in the conserved oligomeric Golgi (COG) complex that orchestrates SNARE-mediated tethering/fusion of vesicles that recycle the Golgi's glycosylation machinery...
Deficiency in the conserved oligomeric Golgi (COG) complex that orchestrates SNARE-mediated tethering/fusion of vesicles that recycle the Golgi's glycosylation machinery results in severe glycosylation defects. Although two major Golgi v-SNAREs, GS28/GOSR1, and GS15/BET1L, are depleted in COG-deficient cells, the complete knockout of GS28 and GS15 only modestly affects Golgi glycosylation, indicating the existence of an adaptation mechanism in Golgi SNARE. Indeed, quantitative mass-spectrometry analysis of STX5-interacting proteins revealed two novel Golgi SNARE complexes-STX5/SNAP29/VAMP7 and STX5/VTI1B/STX8/YKT6. These complexes are present in wild-type cells, but their usage is significantly increased in both GS28- and COG-deficient cells. Upon GS28 deletion, SNAP29 increased its Golgi residency in a STX5-dependent manner. While STX5 depletion and Retro2-induced diversion from the Golgi severely affect protein glycosylation, GS28/SNAP29 and GS28/VTI1B double knockouts alter glycosylation similarly to GS28 KO, indicating that a single STX5-based SNARE complex is sufficient to support Golgi glycosylation. Importantly, co-depletion of three Golgi SNARE complexes in GS28/SNAP29/VTI1B TKO cells resulted in severe glycosylation defects and a reduced capacity for glycosylation enzyme retention at the Golgi. This study demonstrates the remarkable plasticity in SXT5-mediated membrane trafficking, uncovering a novel adaptive response to the failure of canonical intra-Golgi vesicle tethering/fusion machinery.
Topics: Qa-SNARE Proteins; Golgi Apparatus; SNARE Proteins
PubMed: 37340984
DOI: 10.1111/tra.12903 -
International Journal of Molecular... Jan 2020Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle... (Review)
Review
Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation.
Topics: Gene Amplification; Gene Expression Regulation, Neoplastic; Golgi Apparatus; Humans; Membrane Proteins; Neoplasms; Prognosis; Up-Regulation
PubMed: 32023813
DOI: 10.3390/ijms21030933 -
Current Opinion in Cell Biology Aug 2020Virtually all transport events at the Golgi complex are regulated by Arf and Rab family GTPases. Recent work has advanced our knowledge regarding the mechanisms... (Review)
Review
Virtually all transport events at the Golgi complex are regulated by Arf and Rab family GTPases. Recent work has advanced our knowledge regarding the mechanisms controlling GTPase activity, and it has become clear that GTPases do not act in isolation but rather function in complex networks of crosstalk and feedback. Together with earlier findings, these recent studies indicate that communication between GTPases, their regulatory proteins, effectors, and lipids plays a pivotal role in Golgi transport and cisternal maturation.
Topics: Cell Membrane; GTP Phosphohydrolases; Golgi Apparatus; Humans; Models, Biological; Phosphorylation; Protein Transport
PubMed: 32143122
DOI: 10.1016/j.ceb.2020.01.014 -
Viruses Sep 2021A variety of immunolabeling procedures for both light and electron microscopy were used to examine the cellular origins of the host membranes supporting the SARS-CoV-2...
A variety of immunolabeling procedures for both light and electron microscopy were used to examine the cellular origins of the host membranes supporting the SARS-CoV-2 replication complex. The endoplasmic reticulum has long been implicated as a source of membrane for the coronavirus replication organelle. Using dsRNA as a marker for sites of viral RNA synthesis, we provide additional evidence supporting ER as a prominent source of membrane. In addition, we observed a rapid fragmentation of the Golgi apparatus which is visible by 6 h and complete by 12 h post-infection. Golgi derived lipid appears to be incorporated into the replication organelle although protein markers are dispersed throughout the infected cell. The mechanism of Golgi disruption is undefined, but chemical disruption of the Golgi apparatus by brefeldin A is inhibitory to viral replication. A search for an individual SARS-CoV-2 protein responsible for this activity identified at least five viral proteins, M, S, E, Orf6, and nsp3, that induced Golgi fragmentation when expressed in eukaryotic cells. Each of these proteins, as well as nsp4, also caused visible changes to ER structure as shown by correlative light and electron microscopy (CLEM). Collectively, these results imply that specific disruption of the Golgi apparatus is a critical component of coronavirus replication.
Topics: Animals; Chlorocebus aethiops; Coronavirus M Proteins; Endoplasmic Reticulum; Golgi Apparatus; Humans; Intracellular Membranes; Microscopy, Electron; SARS-CoV-2; Vero Cells; Viral Structural Proteins; Virus Replication
PubMed: 34578379
DOI: 10.3390/v13091798 -
Trends in Cell Biology Oct 2020Classically, animal cells nucleate or form new microtubules off the perinuclear centrosome. In recent years, the Golgi outpost has emerged as a satellite organelle that... (Review)
Review
Classically, animal cells nucleate or form new microtubules off the perinuclear centrosome. In recent years, the Golgi outpost has emerged as a satellite organelle that can function as an acentrosomal microtubule-organizing center (MTOC), nucleating new microtubules at distances far from the nucleus or cell body. Golgi outposts can nucleate new microtubules in specialized cells with unique cytoarchitectures, including Drosophila neurons, mouse muscle cells, and rodent oligodendrocytes. This review compares and contrasts topics of functional relevance, including Golgi outpost heterogeneity, formation and transport, as well as regulation of microtubule polarity and branching. Golgi outposts have also been implicated in the pathology of diseases including muscular dystrophy, and neurodegenerative diseases, such as Parkinson's disease (PD). Since Golgi outposts are relatively understudied, many outstanding questions regarding their function and roles in disease remain.
Topics: Aging; Animals; Dendrites; Disease; Golgi Apparatus; Humans; Microtubules; Muscle Cells
PubMed: 32863092
DOI: 10.1016/j.tcb.2020.07.004 -
Archives of Pharmacal Research Oct 2022The Golgi apparatus is an essential cellular organelle that mediates homeostatic functions, including vesicle trafficking and the post-translational modification of... (Review)
Review
The Golgi apparatus is an essential cellular organelle that mediates homeostatic functions, including vesicle trafficking and the post-translational modification of macromolecules. Its unique stacked structure and dynamic functions are tightly regulated, and several Golgi proteins play key roles in the functioning of unconventional protein secretory pathways triggered by cellular stress responses. Recently, an increasing number of studies have implicated defects in Golgi functioning in human diseases such as cancer, neurodegenerative, and immunological disorders. Understanding the extraordinary characteristics of Golgi proteins is important for elucidating its associated intracellular signaling mechanisms and has important ramifications for human health. Therefore, analyzing the mechanisms by which the Golgi participates in disease pathogenesis may be useful for developing novel therapeutic strategies. This review articulates the structural features and abnormalities of the Golgi apparatus reported in various diseases and the suspected mechanisms underlying the Golgi-associated pathologies. Furthermore, we review the potential therapeutic strategies based on Golgi function.
Topics: Humans; Golgi Apparatus; Proteins; Protein Processing, Post-Translational; Homeostasis
PubMed: 36178581
DOI: 10.1007/s12272-022-01408-z