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Science Advances Apr 2023Intracellular G protein-coupled receptors (GPCRs) can be activated by permeant ligands, which contributes to agonist selectivity. Opioid receptors (ORs) provide a...
Intracellular G protein-coupled receptors (GPCRs) can be activated by permeant ligands, which contributes to agonist selectivity. Opioid receptors (ORs) provide a notable example, where opioid drugs rapidly activate ORs in the Golgi apparatus. Our knowledge on intracellular GPCR function remains incomplete, and it is unknown whether OR signaling in plasma membrane (PM) and Golgi apparatus differs. Here, we assess the recruitment of signal transducers to mu- and delta-ORs in both compartments. We find that Golgi ORs couple to Gαi/o probes and are phosphorylated but, unlike PM receptors, do not recruit β-arrestin or a specific Gα probe. Molecular dynamics simulations with OR-transducer complexes in bilayers mimicking PM or Golgi composition reveal that the lipid environment promotes the location-selective coupling. We then show that delta-ORs in PM and Golgi have distinct effects on transcription and protein phosphorylation. The study reveals that the subcellular location defines the signaling effects of opioid drugs.
Topics: Analgesics, Opioid; Signal Transduction; Receptors, G-Protein-Coupled; Cell Membrane; Golgi Apparatus
PubMed: 37075112
DOI: 10.1126/sciadv.adf6059 -
Molecular and Cellular Biology 2023The highly conserved retromer complex controls the fate of hundreds of receptors that pass through the endolysosomal system and is a central regulatory node for diverse... (Review)
Review
The highly conserved retromer complex controls the fate of hundreds of receptors that pass through the endolysosomal system and is a central regulatory node for diverse metabolic programs. More than 20 years ago, retromer was discovered as an essential regulator of endosome-to-Golgi transport in yeast; since then, significant progress has been made to characterize how metazoan retromer components assemble to enable its engagement with endosomal membranes, where it sorts cargo receptors from endosomes to the -Golgi network or plasma membrane through recognition of sorting motifs in their cytoplasmic tails. In this review, we examine retromer regulation by exploring its assembled structure with an emphasis on how a range of adaptor proteins shape the process of receptor trafficking. Specifically, we focus on how retromer is recruited to endosomes, selects cargoes, and generates tubulovesicular carriers that deliver cargoes to target membranes. We also examine how cells adapt to distinct metabolic states by coordinating retromer expression and function. We contrast similarities and differences between retromer and its related complexes: retriever and commander/CCC, as well as their interplay in receptor trafficking. We elucidate how loss of retromer regulation is central to the pathology of various neurogenerative and metabolic diseases, as well as microbial infections, and highlight both opportunities and cautions for therapeutics that target retromer. Finally, with a focus on understanding the mechanisms that govern retromer regulation, we outline new directions for the field moving forward.
Topics: Animals; Golgi Apparatus; trans-Golgi Network; Protein Transport; Cell Membrane; Endosomes; Saccharomyces cerevisiae
PubMed: 37350516
DOI: 10.1080/10985549.2023.2222053 -
Cells Sep 2022The Golgi apparatus (GA) is essential for intracellular sorting, trafficking and the targeting of proteins to specific cellular compartments. Anatomically, the GA... (Review)
Review
The Golgi apparatus (GA) is essential for intracellular sorting, trafficking and the targeting of proteins to specific cellular compartments. Anatomically, the GA spreads all over the cell but is also particularly enriched close to the base of the primary cilium. This peculiar organelle protrudes at the surface of almost all cells and fulfills many cellular functions, in particular during development, when a dysfunction of the primary cilium can lead to disorders called ciliopathies. While ciliopathies caused by loss of ciliated proteins have been extensively documented, several studies suggest that alterations of GA and GA-associated proteins can also affect ciliogenesis. Here, we aim to discuss how the loss-of-function of genes coding these proteins induces ciliary defects and results in ciliopathies.
Topics: Cell Movement; Cilia; Ciliopathies; Golgi Apparatus; Humans; Organelles
PubMed: 36139347
DOI: 10.3390/cells11182773 -
International Journal of Molecular... Apr 2023Today, the future paradigm of intracellular transport could be based on four competing models, namely the vesicular model, the cisterna maturation-progression model, the...
Today, the future paradigm of intracellular transport could be based on four competing models, namely the vesicular model, the cisterna maturation-progression model, the diffusion model, and the kiss-and-run model [...].
Topics: Golgi Apparatus; Biological Transport; Diffusion; Intracellular Membranes
PubMed: 37108712
DOI: 10.3390/ijms24087549 -
Immunity Mar 2023STING transverses the endoplasmic reticulum (ER), Golgi, and endosomal compartments before its degradation within the lysosomes. In this issue of Immunity, Fang et al....
STING transverses the endoplasmic reticulum (ER), Golgi, and endosomal compartments before its degradation within the lysosomes. In this issue of Immunity, Fang et al. demonstrate that the enrichment of cholesterol and sphingomyelin in the trans-Golgi network and endosomes mediated by the ARMH3-PI4KB-PI4P pathway plays a pivotal role in STING activation under cGAS-dependent and -independent conditions.
Topics: Golgi Apparatus; Nucleotidyltransferases; Endosomes; Lysosomes; Immunity, Innate
PubMed: 36921569
DOI: 10.1016/j.immuni.2023.02.012 -
Scientific Reports Sep 2022Retro-2 directly interacts with an ER exit site protein, Sec16A, inhibiting ER exit of a Golgi tSNARE, Syntaxin5, which results in rapid re-distribution of Syntaxin5 to...
Retro-2 directly interacts with an ER exit site protein, Sec16A, inhibiting ER exit of a Golgi tSNARE, Syntaxin5, which results in rapid re-distribution of Syntaxin5 to the ER. Recently, it was shown that SARS-CoV-2 infection disrupts the Golgi apparatus within 6-12 h, while its replication was effectively inhibited by Retro-2 in cultured human lung cells. Yet, exactly how Retro-2 may influence ultrastructure of the Golgi apparatus have not been thoroughly investigated. In this study, we characterized the effect of Retro-2 treatment on ultrastructure of the Golgi apparatus using electron microscopy and EM tomography. Our initial results on protein secretion showed that Retro-2 treatment does not significantly influence secretion of either small or large cargos. Ultra-structural study of the Golgi, however, revealed rapid accumulation of COPI-like vesicular profiles in the perinuclear area and a partial disassembly of the Golgi stack under electron microscope within 3-5 h, suggesting altered Golgi organization in these cells. Retro-2 treatment in cells depleted of GRASP65/55, the two well-known Golgi structural proteins, induced complete and rapid disassembly of the Golgi into individual cisterna. Taken together, these results suggest that Retro-2 profoundly alters Golgi structure to a much greater extent than previously anticipated.
Topics: COVID-19; Endoplasmic Reticulum; Golgi Apparatus; Humans; SARS-CoV-2; Vesicular Transport Proteins
PubMed: 36056100
DOI: 10.1038/s41598-022-19415-x -
IUBMB Life Apr 2022Organelles can easily be disrupted by intracellular and extracellular factors. Studies on ER and mitochondria indicate that a wide range of responses are elicited upon...
Organelles can easily be disrupted by intracellular and extracellular factors. Studies on ER and mitochondria indicate that a wide range of responses are elicited upon organelle disruption. One response thought to be of particular importance is autophagy. Cells can target entire organelles into autophagosomes for removal. This wholesale nature makes autophagy a robust means for eliminating compromised organelles. Recently, it was demonstrated that the Golgi apparatus is a substrate of autophagy. On the other hand, various reports have shown that components traffic away from the Golgi for elimination in an autophagosome-independent manner when the Golgi apparatus is stressed. Future studies will reveal how these different pieces of machinery coordinate to drive Golgi degradation. Quantitative measurements will be needed to determine how much autophagy contributes to the maintenance of the Golgi apparatus.
Topics: Autophagosomes; Autophagy; Endoplasmic Reticulum; Golgi Apparatus; Quality Control
PubMed: 35274438
DOI: 10.1002/iub.2611 -
The Plant Cell Sep 2019
Topics: Endoplasmic Reticulum; Golgi Apparatus
PubMed: 31266848
DOI: 10.1105/tpc.19.00477 -
Current Opinion in Cell Biology Oct 2022Both neurons and glia in mammalian brains are highly ramified. Neurons form complex neural networks using axons and dendrites. Axons are long with few branches and form... (Review)
Review
Both neurons and glia in mammalian brains are highly ramified. Neurons form complex neural networks using axons and dendrites. Axons are long with few branches and form pre-synaptic boutons that connect to target neurons and effector tissues. Dendrites are shorter, highly branched, and form post-synaptic boutons. Astrocyte processes contact synapses and blood vessels in order to regulate neuronal activity and blood flow, respectively. Oligodendrocyte processes extend toward axons to make myelin sheaths. Microglia processes dynamically survey their environments. Here, we describe the local secretory system (ER and Golgi) in neuronal and glial processes. We focus on Golgi outpost functions in acentrosomal microtubule nucleation, cargo trafficking, and protein glycosylation. Thus, satellite ER and Golgi are critical for local structure and function in neurons and glia.
Topics: Animals; Axons; Dendrites; Golgi Apparatus; Mammals; Neurons; Synapses
PubMed: 35964523
DOI: 10.1016/j.ceb.2022.102119 -
FEBS Letters Sep 2019Organelles have been studied traditionally as single units, but a novel concept is now emerging: each organelle has distinct functional zones that regulate specific... (Review)
Review
Organelles have been studied traditionally as single units, but a novel concept is now emerging: each organelle has distinct functional zones that regulate specific functions. The Golgi apparatus seems to have various zones, including zones for: glycosylphosphatidylinositol-anchored proteins; proteoglycan, mucin and lipid glycosylation; transport of cholesterol and ceramides; protein degradation (Golgi membrane-associated degradation); and signalling for apoptosis. The capacity for these specific functions and the size of the corresponding zones appear to be tightly regulated by the Golgi stress response to accommodate cellular demands. For instance, the proteoglycan and mucin zones seem to be separately augmented during the differentiation of chondrocytes and goblet cells, respectively. The mammalian Golgi stress response consists of several response pathways. The TFE3 pathway regulates the general function of the Golgi, such as structural maintenance, N-glycosylation and vesicular transport, whereas the proteoglycan pathway increases the expression of glycosylation enzymes for proteoglycans. The CREB3 and HSP47 pathways regulate pro- and anti-apoptotic functions, respectively. These observations indicate that the Golgi is a dynamic organelle, the capacity of which is upregulated according to cellular needs.
Topics: Animals; Endoplasmic Reticulum Stress; Golgi Apparatus; Humans
PubMed: 31344260
DOI: 10.1002/1873-3468.13554