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1
Schmidt, W. K., and H. P. Moore. "Ionic milieu controls the compartment-specific activation of pro-opiomelanocortin processing in AtT-20 cells." Molecular Biology of the Cell 6, no. 10 (October 1995): 1271–85. http://dx.doi.org/10.1091/mbc.6.10.1271.
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Newly synthesized prohormones and their processing enzymes transit through the same compartments before being packaged into regulated secretory granules. Despite this coordinated intracellular transport, prohormone processing does not occur until late in the secretory pathway. In the mouse pituitary AtT-20 cell line, conversion of pro-opiomelanocortin (POMC) to mature adrenocorticotropic hormone involves the prohormone convertase PC1. The mechanism by which this proteolytic processing is restricted to late secretory compartments is unknown; PC1 activity could be regulated by compartment-specific activators/inhibitors, or through changes in the ionic milieu that influence its activity. By arresting transport in a semi-intact cell system, we have addressed whether metabolically labeled POMC trapped in early secretory compartments can be induced to undergo conversion if the ionic milieu in these compartments is experimentally manipulated. Prolonged incubation of labeled POMC trapped in the endoplasmic reticulum or Golgi/trans-Golgi network did not result in processing, thereby supporting the theory that processing is normally a post-Golgi/trans-Golgi network event. However, acidification of these compartments allowed effective processing of POMC to the intermediate and mature forms. The observed processing increased sharply at a pH below 6.0 and required millimolar calcium, regardless of the compartment in which labeled POMC resided. These conditions also resulted in the coordinate conversion of PC1 from the 84/87 kDa into the 74-kDa and 66-kDa forms. We propose that POMC processing is predominantly restricted to acidifying secretory granules, and that a change in pH within these granules is both necessary and sufficient to activate POMC processing.
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Derré, Isabelle, and Ralph R. Isberg. "LidA, a Translocated Substrate of the Legionella pneumophila Type IV Secretion System, Interferes with the Early Secretory Pathway." Infection and Immunity 73, no. 7 (July 2005): 4370–80. http://dx.doi.org/10.1128/iai.73.7.4370-4380.2005.
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ABSTRACT Legionella pneumophila uses a type IV secretion system to deliver effector molecules into the host cell and establish its replication vacuole. In this study, we investigated the role of LidA, a translocated substrate associated with the surface of the L. pneumophila-containing vacuole. LidA is secreted into the host cell throughout the replication cycle of the bacteria and associates with compartments of the early secretory pathway. When overexpressed in mammalian cells or yeast, LidA interferes with the early secretory pathway, probably via a domain predicted to be rich in coiled-coil structure. Finally, during intracellular replication, the replication vacuoles are in close contact with the endoplasmic reticulum-Golgi intermediate compartment and the Golgi apparatus, suggesting a positive correlation between intracellular growth and association of the vacuole with compartments of the early secretory pathway. We propose that LidA is involved in the recruitment of early secretory vesicles to the L. pneumophila-containing vacuole and that the vacuole associates with the secretory pathway to facilitate this process.
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Tobin, V. A., and M. Ludwig. "The actin filament and dendritic peptide release." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1243–46. http://dx.doi.org/10.1042/bst0351243.
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F-actin remodelling has been implicated in regulated secretion from many cell types, in particular secretion from neuron axon terminals and neuroendocrine cell types. Cortical F-actin has long been postulated to act as a barrier to vesicle movement and hence to inhibit secretion; however, more recent studies point to F-actin remodelling providing both supporting and restraining roles in secretion. Magnocellular neurons of the supraoptic nucleus secrete either oxytocin or vasopressin from their dendrites as well as their axon terminals; and peptide release from these two compartments can be differentially controlled to allow secretion from one compartment in isolation from the other. While oxytocin and vasopressin secretion can be provoked by F-actin depolymerization in both compartments, acutely stimulated secretion is dependent on F-actin remodelling in dendrites but not axon terminals, suggesting that F-actin plays a different role in regulating the readily releasable pool of secretory vesicles in the two compartments. In addition, activity-dependent secretion from the dendritic compartment can be primed by prior exposure to agents, including oxytocin, that stimulate release of Ca2+ from intracellular stores. While remodelling of F-actin is involved, it is not solely responsible for priming secretory responses.
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Bianco, P., M. Riminucci, E. Bonucci, J. D. Termine, and P. G. Robey. "Bone sialoprotein (BSP) secretion and osteoblast differentiation: relationship to bromodeoxyuridine incorporation, alkaline phosphatase, and matrix deposition." Journal of Histochemistry & Cytochemistry 41, no. 2 (February 1993): 183–91. http://dx.doi.org/10.1177/41.2.8419458.
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We defined two distinct maturational compartments (proliferative and secretory) of osteogenic cells in vivo on the basis of ALP activity, BrdU incorporation, cell shape, and BSP production. BSP immunoreactivity was found to mark cells in the secretory but not in the proliferative compartment. We established the phenotypic similarity of primitive marrow stromal cells with proliferating perichondral cells (fibroblast-like, ALP+, BrdU+, BSP-). This suggests the potential functional equivalence of the two cell types as committed non-secretory osteogenic cells and points to the duality of osteogenic cell compartments as a generalized feature of bone formation. We further showed that although BSP secretion is a hallmark of the onset of osteogenesis, BSP antigenicity is lost both in osteoid and in a large proportion of mature osteoblasts during subsequent phases of bone deposition. This suggests that bone formation may not be a uniform event, as bone cells actually deposit antigenically, and likely biochemically, distinct matrices at specific times.
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Naik, Haley B., Melissa Beshire, Breda M. Walsh, Jingjing Liu, and David I. Soybel. "Secretory state regulates Zn2+ transport in gastric parietal cell of the rabbit." American Journal of Physiology-Cell Physiology 297, no. 4 (October 2009): C979—C989. http://dx.doi.org/10.1152/ajpcell.00577.2008.
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Secretory compartments of neurons, endocrine cells, and exocrine glands are acidic and contain high levels of labile Zn2+. Previously, we reported evidence that acidity is regulated, in part, by the content of Zn2+ in the secretory [i.e., tubulovesicle (TV)] compartment of the acid-secreting gastric parietal cell. Here we report studies focusing on the mechanisms of Zn2+ transport by the TV compartment in the mammalian (rabbit) gastric parietal cell. Uptake of Zn2+ by isolated TV structures was monitored with a novel application of the fluorescent Zn2+ reporter N-(6-methoxy-8-quinolyl)- para-toluenesulfonamide (TSQ). Uptake was suppressed by removal of external ATP or blockade of H+-K+-ATPase that mediates luminal acid secretion. Uptake was diminished with dissipation of the proton gradient across the TV membrane, suggesting Zn2+/H+ antiport as the connection between Zn2+ uptake and acidity in the TV lumen. In isolated gastric glands loaded with the reporter fluozin-3, inhibition of H+-K+-ATPase arrested the flow of Zn2+ from the cytoplasm to the TV compartment and secretory stimulation with forskolin enhanced vectorial movement of cytoplasmic Zn2+ into the tubulovesicle/lumen (TV/L) compartment. Our findings suggest that Zn2+ accumulation in the TV/L compartment is physiologically coupled to secretion of acid. These findings offer novel insight into mechanisms regulating Zn2+ homeostasis in the gastric parietal cell and potentially other cells in which acidic subcellular compartments serve signature functional roles.
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Plutner, H., A. D. Cox, S. Pind, R. Khosravi-Far, J. R. Bourne, R. Schwaninger, C. J. Der, and W. E. Balch. "Rab1b regulates vesicular transport between the endoplasmic reticulum and successive Golgi compartments." Journal of Cell Biology 115, no. 1 (October 1, 1991): 31–43. http://dx.doi.org/10.1083/jcb.115.1.31.
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We report an essential role for the ras-related small GTP-binding protein rab1b in vesicular transport in mammalian cells. mAbs detect rab1b in both the ER and Golgi compartments. Using an assay which reconstitutes transport between the ER and the cis-Golgi compartment, we find that rab1b is required during an initial step in export of protein from the ER. In addition, it is also required for transport of protein between successive cis- and medial-Golgi compartments. We suggest that rab1b may provide a common link between upstream and downstream components of the vesicular fission and fusion machinery functioning in early compartments of the secretory pathway.
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Raote, Ishier, and Vivek Malhotra. "Protein transport by vesicles and tunnels." Journal of Cell Biology 218, no. 3 (February 4, 2019): 737–39. http://dx.doi.org/10.1083/jcb.201811073.
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Palade’s corpus placed small vesicles as the sole means to transport proteins across stable distinct compartments of the secretory pathway. We suggest that cargo, spatial organization of secretory compartments, and the timing of fission of cargo-filled containers dictate the design of transport intermediates that can be vesicles and transient direct tunnels.
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Diekwisch, Thomas G. H. "Subunit Compartments of Secretory Stage Enamel Matrix." Connective Tissue Research 38, no. 1-4 (January 1998): 101–11. http://dx.doi.org/10.3109/03008209809017026.
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Saraste, Jaakko. "Introduction: Enigmatic compartments of the secretory pathway." Seminars in Cell Biology 3, no. 5 (October 1992): 299. http://dx.doi.org/10.1016/1043-4682(92)90016-o.
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Oyarce, A. M., and B. A. Eipper. "Identification of subcellular compartments containing peptidylglycine alpha-amidating monooxygenase in rat anterior pituitary." Journal of Cell Science 108, no. 1 (January 1, 1995): 287–97. http://dx.doi.org/10.1242/jcs.108.1.287.
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Both soluble and integral membrane forms of peptidylglycine alpha-amidating monooxygenase (PAM) are expressed in the rat anterior pituitary, making it an ideal model system for studying the routing of proteins into secretory granules. To identify the subcellular compartments involved in the routing of integral membrane PAM, we used subcellular fractionation, metabolic labeling and immunoblot analysis. Mature secretory granules were found to contain full-length integral membrane PAM along with a significant amount of soluble PAM generated by endoproteolytic cleavage. PAM proteins were not co-distributed with tyrosylprotein sulfotransferase activity during sucrose gradient centrifugation, indicating that the trans-Golgi/TGN is not a major PAM-containing compartment at steady state. Fractionation of the 4,000 g and 10,000 g pellets obtained by differential centrifugation identified a significant amount of integral membrane PAM in a light fraction lacking soluble secretory granule proteins. Metabolic labeling experiments with primary anterior pituitary cells demonstrated that integral membrane PAM enters a light compartment with similar properties only after exit from the trans-Golgi/TGN. Comparison of the metabolic labeling and immunoblot analyses suggests that PAM in this post-trans-Golgi/TGN compartment is in organelles involved in the intracellular recycling of integral membrane PAM. Small amounts of full-length integral membrane PAM were also recovered in fractions containing internalized transferrin and may be in an endosomal compartment following retrieval from the cell surface.
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Messenger, Scott W., Diana D. H. Thomas, Michelle A. Falkowski, Jennifer A. Byrne, Fred S. Gorelick, and Guy E. Groblewski. "Tumor protein D52 controls trafficking of an apical endolysosomal secretory pathway in pancreatic acinar cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 6 (September 15, 2013): G439—G452. http://dx.doi.org/10.1152/ajpgi.00143.2013.
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Zymogen granule (ZG) formation in acinar cells involves zymogen cargo sorting from trans-Golgi into immature secretory granules (ISGs). ISG maturation progresses by removal of lysosomal membrane and select content proteins, which enter endosomal intermediates prior to their apical exocytosis. Constitutive and stimulated secretion through this mechanism is termed the constitutive-like and minor-regulated pathways, respectively. However, the molecular components that control membrane trafficking within these endosomal compartments are largely unknown. We show that tumor protein D52 is highly expressed in endosomal compartments following pancreatic acinar cell stimulation and regulates apical exocytosis of an apically directed endolysosomal compartment. Secretion from the endolysosomal compartment was detected by cell-surface antigen labeling of lysosome-associated membrane protein LAMP1, which is absent from ZGs, and had incomplete overlap with surface labeling of synaptotagmin 1, a marker of ZG exocytosis. Although culturing (16–18 h) of isolated acinar cells is accompanied by a loss of secretory responsiveness, the levels of SNARE proteins necessary for ZG exocytosis were preserved. However, levels of endolysosomal proteins D52, EEA1, Rab5, and LAMP1 markedly decreased with culture. When D52 levels were restored by adenoviral delivery, the levels of these regulatory proteins and secretion of both LAMP1 (endolysosomal) and amylase was strongly enhanced. These secretory effects were absent in alanine and aspartate substitutions of serine 136, the major D52 phosphorylation site, and were inhibited by brefeldin A, which does not directly affect the ZG compartment. Our results indicate that D52 directly regulates apical endolysosomal secretion and are consistent with previous studies, suggesting that this pathway indirectly regulates ZG secretion of digestive enzymes.
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Wassmer, Thomas, Roland Kissmehl, Jean Cohen, and Helmut Plattner. "Seventeen a-Subunit Isoforms of Paramecium V-ATPase Provide High Specialization in Localization and Function." Molecular Biology of the Cell 17, no. 2 (February 2006): 917–30. http://dx.doi.org/10.1091/mbc.e05-06-0511.
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In the Paramecium tetraurelia genome, 17 genes encoding the 100-kDa-subunit (a-subunit) of the vacuolar-proton-ATPase were identified, representing by far the largest number of a-subunit genes encountered in any organism investigated so far. They group into nine clusters, eight pairs with >82% amino acid identity and one single gene. Green fluorescent protein-tagging of representatives of the nine clusters revealed highly specific targeting to at least seven different compartments, among them dense core secretory vesicles (trichocysts), the contractile vacuole complex, and phagosomes. RNA interference for two pairs confirmed their functional specialization in their target compartments: silencing of the trichocyst-specific form affected this secretory pathway, whereas silencing of the contractile vacuole complex-specific form altered organelle structure and functioning. The construction of chimeras between selected a-subunits surprisingly revealed the targeting signal to be located in the C terminus of the protein, in contrast with the N-terminal targeting signal of the a-subunit in yeast. Interestingly, some chimeras provoked deleterious effects, locally in their target compartment, or remotely, in the compartment whose specific a-subunit N terminus was used in the chimera.
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Graham, T. R., and S. D. Emr. "Compartmental organization of Golgi-specific protein modification and vacuolar protein sorting events defined in a yeast sec18 (NSF) mutant." Journal of Cell Biology 114, no. 2 (July 15, 1991): 207–18. http://dx.doi.org/10.1083/jcb.114.2.207.
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The sec18 and sec23 secretory mutants of Saccharomyces cerevisiae have previously been shown to exhibit temperature-conditional defects in protein transport from the ER to the Golgi complex (Novick, P., S. Ferro, and R. Schekman, 1981. Cell. 25:461-469). We have found that the Sec18 and Sec23 protein functions are rapidly inactivated upon shifting mutant cells to the nonpermissive temperature (less than 1 min). This has permitted an analysis of the potential role these SEC gene products play in transport events distal to the ER. The sec-dependent transport of alpha-factor (alpha f) and carboxypeptidase Y (CPY) biosynthetic intermediates present throughout the secretory pathway was monitored in temperature shift experiments. We found that Sec18p/NSF function was required sequentially for protein transport from the ER to the Golgi complex, through multiple Golgi compartments and from the Golgi complex to the cell surface. In contrast, Sec23p function was required in the Golgi complex, but only for transport of alpha f out of an early compartment. Together, these studies define at least three functionally distinct Golgi compartments in yeast. From cis to trans these compartments contain: (a) An alpha 1----6 mannosyltransferase; (b) an alpha 1----3 mannosyltransferase; and (c) the Kex2 endopeptidase. Surprisingly, we also found that a pool of Golgi-modified CPY (p2 CPY) located in a compartment distal to the alpha 1----3 mannosyltransferase does not require Sec18p function for final delivery to the vacuole. This compartment appears to be equivalent to the Kex2 compartment as we show that a novel vacuolar CPY-alpha f-invertase fusion protein undergoes efficient Kex2-dependent cleavage resulting in the secretion of invertase. We propose that this Kex2 compartment is the site in which vacuolar proteins are sorted from proteins destined to be secreted.
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Kobayashi, T., and J. M. Robinson. "A novel intracellular compartment with unusual secretory properties in human neutrophils." Journal of Cell Biology 113, no. 4 (May 15, 1991): 743–56. http://dx.doi.org/10.1083/jcb.113.4.743.
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Human neutrophils contain a novel intracellular compartment that is distinct from the previously characterized azurophil and specific granules. This compartment is distinguished by the presence of cytochemically detectable alkaline phosphatase activity. The alkaline phosphatase-containing compartments are short rod-shaped organelles that rapidly undergo a dramatic reorganization upon cell stimulation with either a chemoattractant or an active phorbol ester. Biochemical analysis shows that in unstimulated neutrophils the majority of the alkaline phosphatase activity is intracellular, but after stimulation essentially all of this activity becomes associated with the cell surface. The exocytotic pathway is unusual in that these small organelles fuse to form elongated tubular structures before their association with the plasmalemma.
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Raposo, Graça, Danielle Tenza, Salahedine Mecheri, Roger Peronet, Christian Bonnerot, and Catherine Desaymard. "Accumulation of Major Histocompatibility Complex Class II Molecules in Mast Cell Secretory Granules and Their Release upon Degranulation." Molecular Biology of the Cell 8, no. 12 (December 1997): 2631–45. http://dx.doi.org/10.1091/mbc.8.12.2631.
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To investigate the relationship between major histocompatibility complex (MHC) class II compartments, secretory granules, and secretory lysosomes, we analyzed the localization and fate of MHC class II molecules in mast cells. In bone marrow-derived mast cells, the bulk of MHC class II molecules is contained in two distinct compartments, with features of both lysosomal compartments and secretory granules defined by their protein content and their accessibility to endocytic tracers. Type I granules display internal membrane vesicles and are accessed by exogenous molecules after a time lag of 20 min; type II granules are reached by the endocytic tracer later and possess a serotonin-rich electron-dense core surrounded by a multivesicular domain. In these type I and type II granules, MHC class II molecules, mannose-6-phosphate receptors and lysosomal membrane proteins (lamp1 and lamp2) localize to small intralumenal vesicles. These 60–80-nm vesicles are released along with inflammatory mediators during mast cell degranulation triggered by IgE-antigen complexes. These observations emphasize the intimate connection between the endocytic and secretory pathways in cells of the hematopoietic lineage which allows regulated secretion of the contents of secretory lysosomes, including membrane proteins associated with small vesicles.
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Laulagnier, Karine, Nicole L. Schieber, Tanja Maritzen, Volker Haucke, Robert G. Parton, and Jean Gruenberg. "Role of AP1 and Gadkin in the traffic of secretory endo-lysosomes." Molecular Biology of the Cell 22, no. 12 (June 15, 2011): 2068–82. http://dx.doi.org/10.1091/mbc.e11-03-0193.
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Whereas lysosome-related organelles (LRO) of specialized cells display both exocytic and endocytic features, lysosomes in nonspecialized cells can also acquire the property to fuse with the plasma membrane upon an acute rise in cytosolic calcium. Here, we characterize this unconventional secretory pathway in fibroblast-like cells, by monitoring the appearance of Lamp1 on the plasma membrane and the release of lysosomal enzymes into the medium. After sequential ablation of endocytic compartments in living cells, we find that donor membranes primarily derive from a late compartment, but that an early compartment is also involved. Strikingly, this endo-secretory process is not affected by treatments that inhibit endosome dynamics (microtubule depolymerization, cholesterol accumulation, overexpression of Rab7 or its effector Rab-interacting lysosomal protein [RILP], overexpression of Rab5 mutants), but depends on Rab27a, a GTPase involved in LRO secretion, and is controlled by F-actin. Moreover, we find that this unconventional endo-secretory pathway requires the adaptor protein complexes AP1, Gadkin (which recruits AP1 by binding to the γ1 subunit), and AP2, but not AP3. We conclude that a specific fraction of the AP2-derived endocytic pathway is dedicated to secretory purposes under the control of AP1 and Gadkin.
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Orci, L., M. Ravazzola, M. Amherdt, O. Madsen, A. Perrelet, J. D. Vassalli, and R. G. Anderson. "Conversion of proinsulin to insulin occurs coordinately with acidification of maturing secretory vesicles." Journal of Cell Biology 103, no. 6 (December 1, 1986): 2273–81. http://dx.doi.org/10.1083/jcb.103.6.2273.
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Proinsulin is a single polypeptide chain composed of the B and A subunits of insulin joined by the C-peptide region. Proinsulin is converted to insulin during the maturation of secretory vesicles by the action of two proteases and conversion is inhibited by ionophores that disrupted intracellular H+ gradients. To determine if conversion of prohormone to hormone actually occurs in an acidic secretory vesicle, cultured rat islet cells were incubated in the presence of 3-(2,4-dinitroanilino)-3' amino-N-methyldipropylamine (DAMP), a basic congener of dinitrophenol that concentrates in acidic compartments and is retained there after aldehyde fixation. The cells were processed for indirect protein A-gold colocalization of DAMP, using a monoclonal antibody to dinitrophenol, and proinsulin, using a monoclonal antibody that exclusively reacts with the prohormone. The average density of DAMP-specific gold particles in immature secretory vesicles that contained proinsulin was 71/micron 2 (18 times cytoplasmic background), which indicated that this compartment was acidic. However, the density of DAMP-specific gold particles in the insulin-rich mature secretory vesicle averaged 433/micron 2. This suggests that although proinsulin conversion occurs in an acidic compartment, the secretory vesicles become more acidic as they mature. Since the concentration of anti-proinsulin IgG binding in secretory vesicles is inversely proportional to the conversion of proinsulin to insulin, we were able to determine that maturing secretory vesicles had to reach a critical pH before proinsulin conversion occurred.
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Bogan, Jonathan S., and Harvey F. Lodish. "Two Compartments for Insulin-Stimulated Exocytosis in 3t3-L1 Adipocytes Defined by Endogenous Acrp30 and Glut4." Journal of Cell Biology 146, no. 3 (August 9, 1999): 609–20. http://dx.doi.org/10.1083/jcb.146.3.609.
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Insulin stimulates adipose cells both to secrete proteins and to translocate the GLUT4 glucose transporter from an intracellular compartment to the plasma membrane. We demonstrate that whereas insulin stimulation of 3T3-L1 adipocytes has no effect on secretion of the α3 chain of type VI collagen, secretion of the protein hormone adipocyte complement related protein of 30 kD (ACRP30) is markedly enhanced. Like GLUT4, regulated exocytosis of ACRP30 appears to require phosphatidylinositol-3-kinase activity, since insulin-stimulated ACRP30 secretion is blocked by pharmacologic inhibitors of this enzyme. Thus, 3T3-L1 adipocytes possess a regulated secretory compartment containing ACRP30. Whether GLUT4 recycles to such a compartment has been controversial. We present deconvolution immunofluorescence microscopy data demonstrating that the subcellular distributions of ACRP30 and GLUT4 are distinct and nonoverlapping; in contrast, those of GLUT4 and the transferrin receptor overlap. Together with supporting evidence that GLUT4 does not recycle to a secretory compartment via the trans-Golgi network, we conclude that there are at least two compartments that undergo insulin-stimulated exocytosis in 3T3-L1 adipocytes: one for ACRP30 secretion and one for GLUT4 translocation.
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Stephens, Samuel B., and Christopher V. Nicchitta. "Divergent Regulation of Protein Synthesis in the Cytosol and Endoplasmic Reticulum Compartments of Mammalian Cells." Molecular Biology of the Cell 19, no. 2 (February 2008): 623–32. http://dx.doi.org/10.1091/mbc.e07-07-0677.
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In eukaryotic cells, mRNAs encoding signal sequence-bearing proteins undergo translation-dependent trafficking to the endoplasmic reticulum (ER), thereby restricting secretory and integral membrane protein synthesis to the ER compartment. However, recent studies demonstrating that mRNAs encoding cytosolic/nucleoplasmic proteins are represented on ER-bound polyribosomes suggest a global role for the ER in cellular protein synthesis. Here, we examined the steady-state protein synthesis rates and compartmental distribution of newly synthesized proteins in the cytosol and ER compartments. We report that ER protein synthesis rates exceed cytosolic protein synthesis rates by 2.5- to 4-fold; yet, completed proteins accumulate to similar levels in the two compartments. These data suggest that a significant fraction of cytosolic proteins undergo synthesis on ER-bound ribosomes. The compartmental differences in steady-state protein synthesis rates correlated with a divergent regulation of the tRNA aminoacylation/deacylation cycle. In the cytosol, two pathways were observed to compete for aminoacyl-tRNAs—protein synthesis and aminoacyl-tRNA hydrolysis—whereas on the ER tRNA deacylation is tightly coupled to protein synthesis. These findings identify a role for the ER in global protein synthesis, and they suggest models where compartmentalization of the tRNA acylation/deacylation cycle contributes to the regulation of global protein synthesis rates.
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Vellosillo, Tamara, José R. Dinneny, Chris R. Somerville, and David W. Ehrhardt. "TRANVIA (TVA) facilitates cellulose synthase trafficking and delivery to the plasma membrane." Proceedings of the National Academy of Sciences 118, no. 30 (July 21, 2021): e2021790118. http://dx.doi.org/10.1073/pnas.2021790118.
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Cellulose is synthesized at the plasma membrane by cellulose synthase (CESA) complexes (CSCs), which are assembled in the Golgi and secreted to the plasma membrane through the trans-Golgi network (TGN) compartment. However, the molecular mechanisms that guide CSCs through the secretory system and deliver them to the plasma membrane are poorly understood. Here, we identified an uncharacterized gene, TRANVIA (TVA), that is transcriptionally coregulated with the CESA genes required for primary cell wall synthesis. The tva mutant exhibits enhanced sensitivity to cellulose synthesis inhibitors; reduced cellulose content; and defective dynamics, density, and secretion of CSCs to the plasma membrane as compared to wild type. TVA is a plant-specific protein of unknown function that is detected in at least two different intracellular compartments: organelles labeled by markers for the TGN and smaller compartments that deliver CSCs to the plasma membrane. Together, our data suggest that TVA promotes trafficking of CSCs to the plasma membrane by facilitating exit from the TGN and/or interaction of CSC secretory vesicles with the plasma membrane.
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McCaffrey, Kathleen, and Ineke Braakman. "Protein quality control at the endoplasmic reticulum." Essays in Biochemistry 60, no. 2 (October 15, 2016): 227–35. http://dx.doi.org/10.1042/ebc20160003.
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The ER (endoplasmic reticulum) is the protein folding ‘factory’ of the secretory pathway. Virtually all proteins destined for the plasma membrane, the extracellular space or other secretory compartments undergo folding and maturation within the ER. The ER hosts a unique PQC (protein quality control) system that allows specialized modifications such as glycosylation and disulfide bond formation essential for the correct folding and function of many secretory proteins. It is also the major checkpoint for misfolded or aggregation-prone proteins that may be toxic to the cell or extracellular environment. A failure of this system, due to aging or other factors, has therefore been implicated in a number of serious human diseases. In this article, we discuss several key features of ER PQC that maintain the health of the cellular secretome.
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Trifaró, J. M. "Scinderin and cortical F-actin are components of the secretory machinery." Canadian Journal of Physiology and Pharmacology 77, no. 9 (October 10, 1999): 660–71. http://dx.doi.org/10.1139/y99-074.
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Secretory vesicle exocytosis is the mechanism of release of neurotransmitters and neuropeptides. Secretory vesicles are localized in at least two morphologically and functionally distinct compartments: the reserve pool and the release-ready pool. Filamentous actin networks play an important role in this compartmentalization and in the trafficking of vesicles between these compartments. The cortical F-actin network constitutes a barrier (negative clamp) to the movement of secretory vesicles to release sites, and it must be locally disassembled to allow translocation of secretory vesicles in preparation for exocytosis. The disassembly of the cortical F-actin network is controlled by scinderin (a Ca2+-dependent F-actin severing protein) upon activation by Ca2+ entering the cells during stimulation. There are several factors that regulate scinderin activation (i.e., Ca2+ levels, phosphatidylinositol 4,5-bisphosphate (PIP2), etc.). The results suggest that scinderin and the cortical F-actin network are components of the secretory machinery.Key words: F-actin, scinderin, exocytosis, cytoskeleton, chromaffin cell.
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Suzuki, Eisuke, Namino Ogawa, Taka-aki Takeda, Yukina Nishito, Yu-ki Tanaka, Takashi Fujiwara, Mayu Matsunaga, et al. "Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation." Journal of Biological Chemistry 295, no. 17 (March 16, 2020): 5669–84. http://dx.doi.org/10.1074/jbc.ra120.012610.
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Numerous zinc ectoenzymes are metalated by zinc and activated in the compartments of the early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located in these compartments are essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5–ZNT6 heterodimers and ZNT7 homodimers, play critical roles in the activation of zinc ectoenzymes, such as alkaline phosphatases (ALPs), by mobilizing cytosolic zinc into these compartments. However, this process remains incompletely understood. Here, using genetically-engineered chicken DT40 cells, we first determined that Zrt/Irt-like protein (ZIP) transporters that are localized to the compartments of the early secretory pathway play only a minor role in the ALP activation process. These transporters included ZIP7, ZIP9, and ZIP13, performing pivotal functions in maintaining cellular homeostasis by effluxing zinc out of the compartments. Next, using purified ALP proteins, we showed that zinc metalation on ALP produced in DT40 cells lacking ZNT5–ZNT6 heterodimers and ZNT7 homodimers is impaired. Finally, by genetically disrupting both ZNT5 and ZNT7 in human HAP1 cells, we directly demonstrated that the tissue-nonspecific ALP-activating functions of both ZNT complexes are conserved in human cells. Furthermore, using mutant HAP1 cells, we uncovered a previously-unrecognized and unique spatial regulation of ZNT5–ZNT6 heterodimer formation, wherein ZNT5 recruits ZNT6 to the Golgi apparatus to form the heterodimeric complex. These findings fill in major gaps in our understanding of the molecular mechanisms underlying zinc ectoenzyme activation in the compartments of the early secretory pathway.
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Jost, Carolina, Lloyd Klickstein, Erica Wetzler, Anoopa Kumar, and Melvin Berger. "Intracellular Storage and Regulated Plasma Membrane Expression of Human Complement Receptor Type 1 in Rat Basophil Leukemia Cell Transfectants." Blood 92, no. 1 (July 1, 1998): 300–309. http://dx.doi.org/10.1182/blood.v92.1.300.413k29_300_309.
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Polymorphonuclear neutrophils (PMN) contain multiple distinct secretory compartments that are sequentially mobilized during cell activation. Complement receptor type 1 (CR1) is a marker for a readily mobilizable secretory vesicle compartment, which can undergo exocytic fusion with the plasma membrane independently of secretion of traditional granule contents. The basis for the formation of these distinct compartments is incompletely understood. Primary and secondary granules are generated directly from the Golgi complex during different stages of development of the cell, obviating the need for sorting signals for proper packaging of their constituents. To determine whether the secretory vesicles are formed in a similar manner, we studied a stable rat basophilic leukemia cell line (RBL-CR1) transfected with a plasmid containing the cDNA of human CR1 driven by a viral promoter. The CR1 was present primarily intracellularly in small vesicles resembling the CR1 storage pools in resting PMN. Activation of RBL-CR1 resulted in translocation of intracellular CR1 to the plasma membrane, with mobilization requirements different from those of the classical RBL granules. Thus, in RBL-CR1, continuously synthesized CR1 is stored and upregulated in much the same way as in PMN. This suggests that differential timing of gene expression is not essential for proper storage of CR1 and that other sorting mechanisms are involved, which can be studied in RBL-transfectants.
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Meagher, James, René Zellweger, and Luis Filgueira. "Functional Dissociation of the Basolateral Transcytotic Compartment from the Apical Phago-lysosomal Compartment in Human Osteoclasts." Journal of Histochemistry & Cytochemistry 53, no. 5 (May 2005): 665–70. http://dx.doi.org/10.1369/jhc.4a6476.2005.
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Tartrate-resistant acid phosphatase (TRAP) is essential for elimination of Staphylococcus aureus, the main infectious agent responsible for osteomyelitis. This in vitro study investigated uptake and processing of fluorescence-labeled S. aureus by human osteoclasts and dendritic cells. The cells were stained for TRAP and the acidic compartment using a fluorescence-based protocol. In dendritic cells, TRAP and bacteria were colocalized. In osteoclasts, there was no colocalization of bacteria, TRAP, or the acidic compartment, indicating that there are three distinct vesicular compartments: the apical phago-lysosomal compartment, the basal secretory compartment, and the basolateral transcytotic compartment. Dissociation of the TRAP-containing transcytotic vesicles from the apical phago-lysosomal compartment may restrain osteoclasts from eliminating S. aureus.
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Styers, Melanie L., Amber K. O'Connor, Robert Grabski, Estelle Cormet-Boyaka, and Elizabeth Sztul. "Depletion of β-COP reveals a role for COP-I in compartmentalization of secretory compartments and in biosynthetic transport of caveolin-1." American Journal of Physiology-Cell Physiology 294, no. 6 (June 2008): C1485—C1498. http://dx.doi.org/10.1152/ajpcell.00010.2008.
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We have utilized small interfering RNA (siRNA)-mediated depletion of the β-COP subunit of COP-I to explore COP-I function in organellar compartmentalization and protein traffic. Reduction in β-COP levels causes the colocalization of markers for the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), Golgi, trans-Golgi network (TGN), and recycling endosomes in large, globular compartments. The lack of spatial differentiation of these compartments is not due to a general collapse of all cellular organelles since markers for the early endosomes and lysosomes do not redistribute to the common structures. Anterograde trafficking of the transmembrane cargo vesicular stomatitis virus membrane glycoprotein and of a subset of soluble cargoes is arrested within the common globular compartments. Similarly, recycling traffic of transferrin through the common compartment is perturbed. Furthermore, the trafficking of caveolin-1 (Cav1), a structural protein of caveolae, is arrested within the globular structures. Importantly, Cav1 coprecipitates with the γ-subunit of COP-I, suggesting that Cav1 is a COP-I cargo. Our findings suggest that COP-I is required for the compartmentalization of the ERGIC, Golgi, TGN, and recycling endosomes and that COP-I plays a novel role in the biosynthetic transport of Cav1.
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Sengeløv, H., L. Kjeldsen, and N. Borregaard. "Control of exocytosis in early neutrophil activation." Journal of Immunology 150, no. 4 (February 15, 1993): 1535–43. http://dx.doi.org/10.4049/jimmunol.150.4.1535.
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Abstract Exocytosis of human neutrophil secretory vesicles, gelatinase granules, specific granules, and azurophil granules was measured during modulation of the intracellular free calcium concentration. A strict rank order of exocytosis of the four compartments was observed when cytosolic calcium was elevated by an ionophore in Fura-2-loaded cells. The rank order was: secretory vesicles, gelatinase granules, specific granules, and azurophil granules. Secretory vesicles were exceptionally sensitive to cytosolic free calcium, being completely mobilized after small cytosolic calcium transients. Kinetic studies with FMLP or ionomycin as stimulus showed that the same rank order was valid concerning the rate of exocytosis. In contrast to the other granules, a major part of the secretory vesicles were exocytosed after FMLP stimulation when intracellular calcium was chelated with bis-(2-amino-5-methylphenoxy)-ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester. These data indicate that, in contrast to other neutrophil granules, secretory vesicles are mobilized completely after small isolated elevations of cytosolic calcium. On the other hand, complete elimination of the FMLP-derived calcium transient does not inhibit exocytosis of secretory vesicles markedly. Thus, the effect of FMLP on secretory vesicles is signaled via cytosolic free calcium and an alternative pathway activated in parallel. This may be the basis for the unique position of this compartment as a readily mobilizable store of components important in early neutrophil activation.
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Glasser, S. R., J. Julian, G. L. Decker, J. P. Tang, and D. D. Carson. "Development of morphological and functional polarity in primary cultures of immature rat uterine epithelial cells." Journal of Cell Biology 107, no. 6 (December 1, 1988): 2409–23. http://dx.doi.org/10.1083/jcb.107.6.2409.
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The present study describes a culture environment in which luminal epithelial cells isolated from immature rat uteri and cultured on a matrix-coated permeable surface, with separate apical and basal secretory compartments, proliferate to confluence. Subsequently the cells undergo a process of differentiation accompanied by progressive development of functional polarity. Ultrastructural and immunocytochemical evidence verifies the ability of these primary cultures to regain polar organization, separate membrane domains, and form functional tight junctions as demonstrated by the development of transepithelial resistance. The appearance of uvomorulin is restricted to the lateral cell surface. Coordinated indices of functional polarity that develop progressively in post-confluent cultures include the preferential uptake of [35S]methionine from the basal surface and a rise in uterine epithelial cell secretory activity characterized by a progressive preference for apical secretion. The time dependent development of polarity was characterized by differences in the protein profiles of the apical and basolateral secretory compartments. The maintenance of hormone responsiveness by the cultured cells was validated by the secretion of two proteins identified as secretory markers of estrogen response in the intact uterus. The technique of culturing the cells on a matrix-coated permeable surface with separate secretory compartments produces a uterine epithelial cell that morphologically and functionally resembles its in situ equivalent. The culture method and analytical approach used in this present study may be applied to primary cultures of a variety of natural epithelia, which have hitherto proven resistant to more conventional culture methodologies.
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Pakdel, Mehrshad, and Julia von Blume. "Exploring new routes for secretory protein export from the trans-Golgi network." Molecular Biology of the Cell 29, no. 3 (February 2018): 235–40. http://dx.doi.org/10.1091/mbc.e17-02-0117.
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Sorting of soluble proteins for transport to intracellular compartments and for secretion from cells is essential for cell and tissue homeostasis. The trans-Golgi network (TGN) is a major sorting station that sorts secretory proteins into specific carriers to transport them to their final destinations. The sorting of lysosomal hydrolases at the TGN by the mannose 6-phosphate receptor is well understood. The recent discovery of a Ca2+-based sorting of secretory cargo at the TGN is beginning to uncover the mechanism by which cells sort secretory cargoes from Golgi residents and cargoes destined to the other cellular compartments. This Ca2+-based sorting involves the cytoplasmic actin cytoskeleton, which through membrane anchored Ca2+ ATPase SPCA1 and the luminal Ca2+ binding protein Cab45 sorts of a subset of secretory proteins at the TGN. We present this discovery and highlight important challenges that remain unaddressed in the overall pathway of cargo sorting at the TGN.
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Slot, Jan W., Gabriella Garruti, Sally Martin, Viola Oorschot, George Posthuma, Edward W. Kraegen, Ross Laybutt, Gaétan Thibault, and David E. James. "Glucose Transporter (GLUT-4) Is Targeted to Secretory Granules in Rat Atrial Cardiomyocytes." Journal of Cell Biology 137, no. 6 (June 16, 1997): 1243–54. http://dx.doi.org/10.1083/jcb.137.6.1243.
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The insulin-responsive glucose transporter GLUT-4 is found in muscle and fat cells in the transGolgi reticulum (TGR) and in an intracellular tubulovesicular compartment, from where it undergoes insulindependent movement to the cell surface. To examine the relationship between these GLUT-4–containing compartments and the regulated secretory pathway we have localized GLUT-4 in atrial cardiomyocytes. This cell type secretes an antihypertensive hormone, referred to as the atrial natriuretic factor (ANF), in response to elevated blood pressure. We show that GLUT-4 is targeted in the atrial cell to the TGR and a tubulo-vesicular compartment, which is morphologically and functionally indistinguishable from the intracellular GLUT-4 compartment found in other types of myocytes and in fat cells, and in addition to the ANF secretory granules. Forming ANF granules are present throughout all Golgi cisternae but only become GLUT4 positive in the TGR. The inability of cyclohexamide treatment to effect the TGR localization of GLUT-4 indicates that GLUT-4 enters the ANF secretory granules at the TGR via the recycling pathway and not via the biosynthetic pathway. These data suggest that a large proportion of GLUT-4 must recycle via the TGR in insulin-sensitive cells. It will be important to determine if this is the pathway by which the insulin-regulatable tubulo-vesicular compartment is formed.
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Anderson, Timothy J., Sally Martin, Jennifer L. Berka, David E. James, Jan W. Slot, and Jennifer L. Stow. "Distinct localization of renin and GLUT-4 in juxtaglomerular cells of mouse kidney." American Journal of Physiology-Renal Physiology 274, no. 1 (January 1, 1998): F26—F33. http://dx.doi.org/10.1152/ajprenal.1998.274.1.f26.
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The insulin-responsive glucose transporter, GLUT-4, is found primarily in adipocytes and skeletal muscle cells, where it is sequestered in a specialized recycling compartment, from which it can be recruited to the cell surface following insulin stimulation. Lower levels of GLUT-4 are also expressed in other tissues, including the kidney, where it is present particularly in cells of the afferent arteriole and juxtaglomerular apparatus (JGA). The exact nature of GLUT-4-containing compartments and their relationship to other regulated trafficking pathways in different cells are not yet well defined. The trafficking of GLUT-4 has been studied in different cells with regulated secretory pathways, and a recent study shows that, in cardiomyocytes, GLUT-4 is sorted and packaged into multiple regulated pathways (J. W. Slot, G. Garruti, S. Martin, V. Oorschot, G. Pshuma, E. W. Kraegen, R. Laybutt, G. Thibault, and D. E. James. J. Cell Biol. 137: 1243–1254, 1997). In the kidney, cells of the JGA synthesize and secrete their major product, renin, via a well-established, regulated, secretory pathway. These cells also express GLUT-4 and thus offer the potential to directly compare the localization and trafficking of GLUT-4 and renin in a unique cell type. The present study was undertaken to investigate the intracellular distribution of GLUT-4 in mouse kidney cortex and to determine whether GLUT-4 and renin are trafficked in the same or in separate regulated pathways. Ultrathin cryosections of mouse kidney were labeled by the immunogold technique and viewed by electron microscopy, demonstrating the distribution of GLUT-4 in cells of the JGA, afferent arteriole, and distal tubule. In granular cells of the JGA, renin was localized in secretory granules of the regulated secretory pathway, whereas GLUT-4 labeling in the same cells was found in a distinct tubulovesicular compartment located adjacent to the trans-Golgi network. We show that granular cells have separate, morphologically distinct compartments for the sequestration of renin and GLUT-4, providing evidence that there may be distinct pathways for the sorting and trafficking of these two proteins.
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Drouin, Arnaud, Rémi Favier, Jean-Marc Massé, Najet Debili, Alain Schmitt, Carole Elbim, Josette Guichard, Mircea Adam, Marie-Anne Gougerot-Pocidalo, and Elisabeth M. Cramer. "Newly recognized cellular abnormalities in the gray platelet syndrome." Blood 98, no. 5 (September 1, 2001): 1382–91. http://dx.doi.org/10.1182/blood.v98.5.1382.
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The gray platelet syndrome (GPS) is a rare congenital bleeding disorder in which thrombocytopenia is associated with increased platelet size and decreased α-granule content. This report describes 3 new pediatric cases presenting with the classical platelet abnormalities of GPS within one family with normal parents. Examination of blood smears of the 3 patients demonstrated not only gray platelets, but also gray polymorphonuclear neutrophils (PMNs) with decreased or abnormally distributed components of secretory compartments (alkaline phosphatase, CD35, CD11b/CD18). Secondary granules were also decreased in number as assayed by immunoelectron microscopy. These data confirm that the secretory compartments in neutrophils were also deficient in this family. Megakaryocytes (MKs) were cultured from the peripheral blood CD34+ cells of the 3 patients for 14 days, in the presence of thrombopoietin and processed for immunoelectron microscopy. Although von Willebrand factor (vWF) was virtually undetectable in platelets, vWF immunolabeling was conspicuous in cultured maturing MKs, particularly within Golgi saccules, but instead of being packaged in α-granules, it was released into the demarcation membrane system. In contrast, P-selectin followed a more classical pathway. Double-labeling experiments confirmed that vWF was following an intracellular pathway distinct from the one of P-selectin. In these 3 new cases of GPS, the MKs appeared to abnormally process vWF, with secretion into the extracellular space instead of normal α-granule packaging. Furthermore, the secretory compartment of another blood cell line, the neutrophil, was also affected in this family of GPS.
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Porter, Brad W., Christen Y. L. Yuen, and David A. Christopher. "Dual protein trafficking to secretory and non-secretory cell compartments: Clear or double vision?" Plant Science 234 (May 2015): 174–79. http://dx.doi.org/10.1016/j.plantsci.2015.02.013.
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Sanchez, Veronica, Elizabeth Sztul, and William J. Britt. "Human Cytomegalovirus pp28 (UL99) Localizes to a Cytoplasmic Compartment Which Overlaps the Endoplasmic Reticulum-Golgi-Intermediate Compartment." Journal of Virology 74, no. 8 (April 15, 2000): 3842–51. http://dx.doi.org/10.1128/jvi.74.8.3842-3851.2000.
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ABSTRACT Although the assembly of herpesviruses has remained an active area of investigation, considerable controversy continues to surround the cellular location of tegument and envelope acquisition. This controversy is particularly evident when the proposed pathways for α- and β-herpesvirus assembly are compared. We have approached this aspect of human cytomegalovirus (HCMV) assembly, specifically, envelopment, by investigating the intracellular trafficking of viral tegument proteins which localize in the cytoplasms of infected cells. In this study we have demonstrated that the virion tegument protein pp28 (UL99), a true late protein, was membrane associated as a result of myristoylation. A mutation in this protein which prevented incorporation of [3H]myristic acid also altered the detergent solubility and intracellular distribution of the protein when it was expressed in transfected cells. Using a panel of markers for intracellular compartments, we could localize the expression of wild-type pp28 to an intracellular compartment which colocalized with the endoplasmic reticulum-Golgi-intermediate compartment (ERGIC), a dynamic compartment of the secretory pathway which interfaces with both the ER and Golgi apparatus. The localization of this viral tegument protein within an early secretory compartment of the cell provided further evidence that the assembly of the HCMV tegument likely includes a cytoplasmic phase. Because pp28 has been shown to be localized to a cytoplasmic assembly compartment in HCMV-infected cells, our findings also suggested that viral tegument protein interactions within the secretory pathway may have an important role in the assembly of the virion.
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Gomez-Navarro, Natalia, and Elizabeth Miller. "Protein sorting at the ER–Golgi interface." Journal of Cell Biology 215, no. 6 (November 30, 2016): 769–78. http://dx.doi.org/10.1083/jcb.201610031.
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Protein traffic is of critical importance for normal cellular physiology. In eukaryotes, spherical transport vesicles move proteins and lipids from one internal membrane-bound compartment to another within the secretory pathway. The process of directing each individual protein to a specific destination (known as protein sorting) is a crucial event that is intrinsically linked to vesicle biogenesis. In this review, we summarize the principles of cargo sorting by the vesicle traffic machinery and consider the diverse mechanisms by which cargo proteins are selected and captured into different transport vesicles. We focus on the first two compartments of the secretory pathway: the endoplasmic reticulum and Golgi. We provide an overview of the complexity and diversity of cargo adaptor function and regulation, focusing on recent mechanistic discoveries that have revealed insight into protein sorting in cells.
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Kreiner, T., and H. P. Moore. "Membrane traffic between secretory compartments is differentially affected during mitosis." Cell Regulation 1, no. 5 (April 1990): 415–24. http://dx.doi.org/10.1091/mbc.1.5.415.
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Membrane traffic has been shown to be regulated during cell division. In particular, with the use of viral membrane proteins as markers, endoplasmic reticulum (ER)-to-Golgi transport in mitotic cells has been shown to be essentially blocked. However, the effect of mitosis on other steps in the secretory pathway is less clear, because an early block makes examination of following steps difficult. Here, we report studies on the functional characteristics of secretory pathways in mitotic mammalian tissue culture cells by the use of a variety of markers. Chinese hamster ovary cells were transfected with cDNAs encoding secretory proteins. Consistent with earlier results following viral membrane proteins, we found that the overall secretory pathway is nonfunctional in mitotic cells, and a major block to secretion is at the step between ER and Golgi: the overall rate of secretion of human growth hormone is reduced at least 10-fold in mitotic cells, and export of truncated vesicular stomatitis virus G protein from the ER is inhibited to about the same extent, as judged by acquisition of endoglycosidase H resistance. To ascertain the integrity of transport from the trans-Golgi to plasma membrane, we followed the secretion of sulfated glycosaminoglycan (GAG) chains, which are synthesized in the Golgi and thus are not subject to the earlier ER-to-Golgi block. GAG chains are valid markers for the pathway taken by constitutive secretory proteins; both protein secretion and GAG chain secretion are sensitive to treatment with n-ethyl-maleimide and monensin and are blocked at 19 degrees C. We found that the extent of GAG-chain secretion is not altered during mitosis, although the initial rate of secretion is reduced about twofold in mitotic compared with interphase cells. Thus, during mitosis, transport from the trans-Golgi to plasma membrane is much less hindered than ER-to-Golgi traffic. We conclude that transport steps are not affected to the same extent during mitosis.
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Cruz-Garcia, David, Amy J. Curwin, Jean-François Popoff, Caroline Bruns, Juan M. Duran, and Vivek Malhotra. "Remodeling of secretory compartments creates CUPS during nutrient starvation." Journal of Cell Biology 207, no. 6 (December 15, 2014): 695–703. http://dx.doi.org/10.1083/jcb.201407119.
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Upon starvation, Grh1, a peripheral membrane protein located at endoplasmic reticulum (ER) exit sites and early Golgi in Saccharomyces cerevisiae under growth conditions, relocates to a compartment called compartment for unconventional protein secretion (CUPS). Here we report that CUPS lack Golgi enzymes, but contain the coat protein complex II (COPII) vesicle tethering protein Uso1 and the Golgi t-SNARE Sed5. Interestingly, CUPS biogenesis is independent of COPII- and COPI-mediated membrane transport. Pik1- and Sec7-mediated membrane export from the late Golgi is required for complete assembly of CUPS, and Vps34 is needed for their maintenance. CUPS formation is triggered by glucose, but not nitrogen starvation. Moreover, upon return to growth conditions, CUPS are absorbed into the ER, and not the vacuole. Altogether our findings indicate that CUPS are not specialized autophagosomes as suggested previously. We suggest that starvation triggers relocation of secretory and endosomal membranes, but not their enzymes, to generate CUPS to sort and secrete proteins that do not enter, or are not processed by enzymes of the ER–Golgi pathway of secretion.
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Sallese, Michele, Monica Giannotta, and Alberto Luini. "Coordination of the secretory compartments via inter-organelle signalling." Seminars in Cell & Developmental Biology 20, no. 7 (September 2009): 801–9. http://dx.doi.org/10.1016/j.semcdb.2009.04.004.
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Canton, Johnathan, and Peter E. Kima. "Interactions of pathogen-containing compartments with the secretory pathway." Cellular Microbiology 14, no. 11 (August 23, 2012): 1676–86. http://dx.doi.org/10.1111/cmi.12000.
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Pfeffer, Suzanne R. "Rab GTPase localization and Rab cascades in Golgi transport." Biochemical Society Transactions 40, no. 6 (November 21, 2012): 1373–77. http://dx.doi.org/10.1042/bst20120168.
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Rab GTPases are master regulators of membrane traffic. By binding to distinct sets of effector proteins, Rabs catalyse the formation of function-specifying membrane microdomains. They are delivered to membranes by a protein named GDI (guanine-nucleotide-dissociation inhibitor) and are stabilized there after nucleotide exchange by effector binding. In the present mini-review, I discuss what we know about how Rab GTPases are delivered to the correct membrane-bound compartments and how Rab GTPase cascades order Rabs within the secretory and endocytic pathways. Finally, I describe how Rab cascades may establish the distinct compartments of the Golgi complex to permit ordered processing, sorting and secretion of secretory cargoes.
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Anelli, Tiziana, and Paola Panina-Bordignon. "How to Avoid a No-Deal ER Exit." Cells 8, no. 9 (September 7, 2019): 1051. http://dx.doi.org/10.3390/cells8091051.
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Efficiency and fidelity of protein secretion are achieved thanks to the presence of different steps, located sequentially in time and space along the secretory compartment, controlling protein folding and maturation. After entering into the endoplasmic reticulum (ER), secretory proteins attain their native structure thanks to specific chaperones and enzymes. Only correctly folded molecules are allowed by quality control (QC) mechanisms to leave the ER and proceed to downstream compartments. Proteins that cannot fold properly are instead retained in the ER to be finally destined to proteasomal degradation. Exiting from the ER requires, in most cases, the use of coated vesicles, departing at the ER exit sites, which will fuse with the Golgi compartment, thus releasing their cargoes. Protein accumulation in the ER can be caused by a too stringent QC or by ineffective transport: these situations could be deleterious for the organism, due to the loss of the secreted protein, and to the cell itself, because of abnormal increase of protein concentration in the ER. In both cases, diseases can arise. In this review, we will describe the pathophysiology of protein folding and transport between the ER and the Golgi compartment.
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Carmeille, Romain, Porfirio Schiano Lomoriello, Parvathi M. Devarakonda, Jacob A. Kellermeier, and Aoife T. Heaslip. "Actin and an unconventional myosin motor, TgMyoF, control the organization and dynamics of the endomembrane network in Toxoplasma gondii." PLOS Pathogens 17, no. 2 (February 2, 2021): e1008787. http://dx.doi.org/10.1371/journal.ppat.1008787.
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Toxoplasma gondii is an obligate intracellular parasite that relies on three distinct secretory organelles, the micronemes, rhoptries, and dense granules, for parasite survival and disease pathogenesis. Secretory proteins destined for these organelles are synthesized in the endoplasmic reticulum (ER) and sequentially trafficked through a highly polarized endomembrane network that consists of the Golgi and multiple post-Golgi compartments. Currently, little is known about how the parasite cytoskeleton controls the positioning of the organelles in this pathway, or how vesicular cargo is trafficked between organelles. Here we show that F-actin and an unconventional myosin motor, TgMyoF, control the dynamics and organization of the organelles in the secretory pathway, specifically ER tubule movement, apical positioning of the Golgi and post-Golgi compartments, apical positioning of the rhoptries, and finally, the directed transport of Rab6-positive and Rop1-positive vesicles. Thus, this study identifies TgMyoF and actin as the key cytoskeletal components that organize the endomembrane system in T. gondii.
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Kuiper, Roland P., and Gerard JM Martens. "Prohormone transport through the secretory pathway of neuroendocrine cells." Biochemistry and Cell Biology 78, no. 3 (April 2, 2000): 289–98. http://dx.doi.org/10.1139/o00-020.
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En route through the secretory pathway of neuroendocrine cells, prohormones pass a series of membrane-bounded compartments. During this transport, the prohormones are sorted to secretory granules and proteolytically cleaved to bioactive peptides. Recently, progress has been made in a number of aspects concerning secretory protein transport and sorting, particularly with respect to transport events in the early regions of the secretory pathway. In this review we will deal with some of these aspects, including: i) selective exit from the endoplasmic reticulum via COPII-coated vesicles and the potential role of p24 putative cargo receptors in this process, ii) cisternal maturation as an alternative model for protein transport through the Golgi complex, and iii) the mechanisms that may be involved in the sorting of regulated secretory proteins to secretory granules. Although much remains to be learned, interesting new insights into the functioning of the secretory pathway have been obtained.Key words: regulated secretory pathway, p24 family, vesicular transport, POMC, protein sorting, secretory granule, Xenopus laevis.
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Canty-Laird, Elizabeth G., Yinhui Lu, and Karl E. Kadler. "Stepwise proteolytic activation of type I procollagen to collagen within the secretory pathway of tendon fibroblasts in situ." Biochemical Journal 441, no. 2 (December 21, 2011): 707–17. http://dx.doi.org/10.1042/bj20111379.
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Proteolytic cleavage of procollagen I to collagen I is essential for the formation of collagen fibrils in the extracellular matrix of vertebrate tissues. Procollagen is cleaved by the procollagen N- and C-proteinases, which remove the respective N- and C-propeptides from procollagen. Procollagen processing is initiated within the secretory pathway in tendon fibroblasts, which are adept in assembling an ordered extracellular matrix of collagen fibrils in vivo. It was thought that intracellular processing was restricted to the TGN (trans-Golgi network). In the present study, brefeldin A treatment of tendon explant cultures showed that N-proteinase activity is present in the resulting fused ER (endoplasmic reticulum)–Golgi compartment, but that C-proteinase activity is restricted to the TGN in embryonic chick tendon fibroblasts. In late embryonic and postnatal rat tail and postnatal mouse tail tendon, C-proteinase activity was detected in TGN and pre-TGN compartments. Preventing activation of the procollagen N- and C-proteinases with the furin inhibitor Dec-RVKR-CMK (decanoyl-Arg-Val-Lys-Arg-chloromethylketone) indicated that only a fraction of intracellular procollagen cleavage was mediated by newly activated proteinases. In conclusion, the N-propeptides are removed earlier in the secretory pathway than the C-propeptides. The removal of the C-propeptides in post-Golgi compartments most probably indicates preparation of collagen molecules for fibril formation at the cell–matrix interface.
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Campoy, Emanuel Martín, Felipe Carlos Martín Zoppino, and María Isabel Colombo. "The Early Secretory Pathway Contributes to the Growth of theCoxiella-Replicative Niche." Infection and Immunity 79, no. 1 (October 11, 2010): 402–13. http://dx.doi.org/10.1128/iai.00688-10.
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ABSTRACTCoxiella burnetiiis a Gram-negative obligate intracellular bacterium. After internalization, this bacterium replicates in a large parasitophorous vacuole that has features of both phagolysosomes and autophagosomal compartments. We have previously demonstrated that early after internalizationCoxiellaphagosomes interact with both the endocytic and the autophagic pathways. In this report, we present evidence that theCoxiella-replicative vacuoles (CRVs) also interact with the secretory pathway. Rab1b is a small GTPase responsible for the anterograde transport between the endoplasmic reticulum and the Golgi apparatus. We present evidence that Rab1b is recruited to the CRV at later infection times (i.e., after 6 h of infection). Interestingly, knockdown of Rab1b altered vacuole growth, indicating that this protein was required for the proper biogenesis of the CRV. In addition, overexpression of the active GTPase-defective mutant (GFP-Rab1b Q67L) affected the development of theCoxiella-replicative compartment inhibiting bacterial growth. On the other hand, disruption of the secretory pathway by brefeldin A treatment or by overexpression of Sar1 T39N, a defective dominant-negative mutant of Sar1, affected the typical spaciousness of the CRVs. Taken together, our results show for the first time that theCoxiella-replicative niche also intercepts the early secretory pathway.
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Burkhardt, J. K., S. Hester, C. K. Lapham, and Y. Argon. "The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments." Journal of Cell Biology 111, no. 6 (December 1, 1990): 2327–40. http://dx.doi.org/10.1083/jcb.111.6.2327.
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Cytolytic lymphocytes contain specialized lytic granules whose secretion during cell-mediated cytolysis results in target cell death. Using serial section EM of RNK-16, a natural killer cell line, we show that there are structurally distinct types of granules. Each type is composed of varying proportions of a dense core domain and a multivesicular cortical domain. The dense core domains contain secretory proteins thought to play a role in cytolysis, including cytolysin and chondroitin sulfate proteoglycan. In contrast, the multivesicular domains contain lysosomal proteins, including acid phosphatase, alpha-glucosidase, cathepsin D, and LGP-120. In addition to their protein content, the lytic granules have other properties in common with lysosomes. The multivesicular regions of the granules have an acidic pH, comparable to that of endosomes and lysosomes. The granules take up exogenous cationized ferritin with lysosome-like kinetics, and this uptake is blocked by weak bases and low temperature. The multivesicular domains of the granules are rich in the 270-kD mannose-6-phosphate receptor, a marker which is absent from mature lysosomes but present in earlier endocytic compartments. Thus, the natural killer granules represent an unusual dual-function organelle, where a regulated secretory compartment, the dense core, is contained within a pre-lysosomal compartment, the multivesicular domain.
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Plutner, H., H. W. Davidson, J. Saraste, and W. E. Balch. "Morphological analysis of protein transport from the ER to Golgi membranes in digitonin-permeabilized cells: role of the P58 containing compartment." Journal of Cell Biology 119, no. 5 (December 1, 1992): 1097–116. http://dx.doi.org/10.1083/jcb.119.5.1097.
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The glycoside digitonin was used to selectively permeabilize the plasma membrane exposing functionally and morphologically intact ER and Golgi compartments. Permeabilized cells efficiently transported vesicular stomatitis virus glycoprotein (VSV-G) through sealed, membrane-bound compartments in an ATP and cytosol dependent fashion. Transport was vectorial. VSV-G protein was first transported to punctate structures which colocalized with p58 (a putative marker for peripheral punctate pre-Golgi intermediates and the cis-Golgi network) before delivery to the medial Golgi compartments containing alpha-1,2-mannosidase II and processing of VSV-G to endoglycosidase H resistant forms. Exit from the ER was inhibited by an antibody recognizing the carboxyl-terminus of VSV-G. In contrast, VSV-G protein colocalized with p58 in the absence of Ca2+ or the presence of an antibody which inhibits the transport component NSF (SEC18). These studies demonstrate that digitonin permeabilized cells can be used to efficiently reconstitute the early secretory pathway in vitro, allowing a direct comparison of the morphological and biochemical events involved in vesicular tafficking, and identifying a key role for the p58 containing compartment in ER to Golgi transport.
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Watson, Robert T., Megumi Furukawa, Shian-Huey Chiang, Diana Boeglin, Makoto Kanzaki, Alan R. Saltiel, and Jeffrey E. Pessin. "The Exocytotic Trafficking of TC10 Occurs through both Classical and Nonclassical Secretory Transport Pathways in 3T3L1 Adipocytes." Molecular and Cellular Biology 23, no. 3 (February 1, 2003): 961–74. http://dx.doi.org/10.1128/mcb.23.3.961-974.2003.
Full textAbstract:
ABSTRACT To examine the structural determinants necessary for TC10 trafficking, localization, and function in adipocytes, we generated a series of point mutations in the carboxyl-terminal targeting domain of TC10. Wild-type TC10 (TC10/WT) localized to secretory membrane compartments and caveolin-positive lipid raft microdomains at the plasma membrane. Expression of a TC10/C206S point mutant resulted in a trafficking and localization pattern that was indistinguishable from that of TC10/WT. In contrast, although TC10/C209S or the double TC10/C206,209S mutant was plasma membrane localized, it was excluded from both the secretory membrane system and the lipid raft compartments. Surprisingly, inhibition of Golgi membrane transport with brefeldin A did not prevent plasma membrane localization of TC10 or H-Ras. Moreover, inhibition of trans-Golgi network exit with a 19°C temperature block did not prevent the trafficking of TC10 or H-Ras to the plasma membrane. These data demonstrate that TC10 and H-Ras can both traffic to the plasma membrane by at least two distinct transport mechanisms in adipocytes, one dependent upon intracellular membrane transport and another independent of the classical secretory membrane system. Moreover, the transport through the secretory pathway is necessary for the localization of TC10 to lipid raft microdomains at the plasma membrane.
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Yang, Tao, Hongtao Zeng, Jian Zhang, Curtis T. Okamoto, Dwight W. Warren, Richard L. Wood, Michael Bachmann, and Austin K. Mircheff. "MHC class II molecules, cathepsins, and La/SSB proteins in lacrimal acinar cell endomembranes." American Journal of Physiology-Cell Physiology 277, no. 5 (November 1, 1999): C994—C1007. http://dx.doi.org/10.1152/ajpcell.1999.277.5.c994.
Full textAbstract:
Sjögren's syndrome is a chronic autoimmune disease affecting the lacrimal glands and other epithelia. It has been suggested that acinar cells of the lacrimal glands provoke local autoimmune responses, leading to Sjögren's syndrome when they begin expressing major histocompatibility complex (MHC) class II molecules. We used isopycnic centrifugation and phase partitioning to resolve compartments that participate in traffic between the basolateral membranes and the endomembrane system to test the hypothesis that MHC class II molecules enter compartments that contain potential autoantigens, i.e., La/SSB, and enzymes capable of proteolytically processing autoantigen, i.e., cathepsins B and D. A series of compartments identified as secretory vesicle membranes, prelysosomes, and microdomains of the trans-Golgi network involved in traffic to the basolateral membrane, to the secretory vesicles, and to the prelysosomes were all prominent loci of MHC class II molecules, La/SSB, and cathepsins B and D. These observations support the thesis that lacrimal gland acinar cells that have been induced to express MHC class II molecules function as autoantigen processing and presenting cells.
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Jones, C. J., and P. M. Quinton. "Dye-coupling compartments in the human eccrine sweat gland." American Journal of Physiology-Cell Physiology 256, no. 3 (March 1, 1989): C478—C485. http://dx.doi.org/10.1152/ajpcell.1989.256.3.c478.
Full textAbstract:
The dye-coupling status of secretory and reabsorptive cells in micro-dissected lengths of human eccrine sweat gland was investigated by means of intracellular microiontophoresis of the fluorescent naphthalimide dye Lucifer yellow CH (Mr 457), which passes through gap junctions. Cells of the reabsorptive duct exhibited complete dye coupling between the apical and basal layers of the epithelium. Conversely, cells of the secretory tubule exhibited selective dye coupling. Of the three cell types present, clear, dark, and myoepithelial, the dark cells were impaled and labeled almost exclusively in the present study. These cells were observed either as single cells or as dye-coupled groups of neighboring dark cells. In no instance were dark cells observed to be dye coupled to clear cells or to myoepithelial cells. Because myoepithelial cells are known to be dye coupled exclusively to neighboring myoepithelial cells, the remaining clear cells must either be uncoupled or show selective dye coupling to neighboring clear cells. The significance of these findings is considered with respect to the regulation and function of the different cell types present in the human eccrine sweat gland.