scholarly journals The Secretory Route of the Leaderless Protein Interleukin 1β Involves Exocytosis of Endolysosome-related Vesicles

1999 ◽  
Vol 10 (5) ◽  
pp. 1463-1475 ◽  
Author(s):  
Cristina Andrei ◽  
Cecilia Dazzi ◽  
Lavinia Lotti ◽  
Maria Rosaria Torrisi ◽  
Giovanna Chimini ◽  
...  
Keyword(s):  
Cathepsin D ◽  
Secretory Protein ◽  
Interleukin 1Β ◽  
Human Monocytes ◽  
Hypotonic Medium ◽  
High Concentration ◽  
Lysosomal Hydrolases ◽  
Late Endosomes ◽  
Medium Increase ◽  
Endocytic Vesicles

Interleukin 1β (IL-1β), a secretory protein lacking a signal peptide, does not follow the classical endoplasmic reticulum-to-Golgi pathway of secretion. Here we provide the evidence for a “leaderless” secretory route that uses regulated exocytosis of preterminal endocytic vesicles to transport cytosolic IL-1β out of the cell. Indeed, although most of the IL-1β precursor (proIL-1β) localizes in the cytosol of activated human monocytes, a fraction is contained within vesicles that cofractionate with late endosomes and early lysosomes on Percoll density gradients and display ultrastructural features and markers typical of these organelles. The observation of organelles positive for both IL-1β and the endolysosomal hydrolase cathepsin D or for both IL-1β and the lysosomal marker Lamp-1 further suggests that they belong to the preterminal endocytic compartment. In addition, similarly to lysosomal hydrolases, secretion of IL-1β is induced by acidotropic drugs. Treatment of monocytes with the sulfonylurea glibenclamide inhibits both IL-1β secretion and vesicular accumulation, suggesting that this drug prevents the translocation of proIL-1β from the cytosol into the vesicles. A high concentration of extracellular ATP and hypotonic medium increase secretion of IL-1β but deplete the vesicular proIL-1β content, indicating that exocytosis of proIL-1β–containing vesicles is regulated by ATP and osmotic conditions.

scholarly journals Mutant Rab7 Causes the Accumulation of Cathepsin D and Cation-independent Mannose 6–Phosphate Receptor in an Early Endocytic Compartment

1998 ◽  
Vol 140 (5) ◽  
pp. 1075-1089 ◽  
Author(s):  
Barry Press ◽  
Yan Feng ◽  
Bernard Hoflack ◽  
Angela Wandinger-Ness
Keyword(s):  
Cathepsin D ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Lysosomal Hydrolases ◽  
Endocytic Compartment ◽  
Lysosome Biogenesis ◽  
Late Endosomes ◽  
Mannose 6 Phosphate ◽  
Lysosomal Membrane Glycoprotein ◽  
Mutant Forms

Stable BHK cell lines inducibly expressing wild-type or dominant negative mutant forms of the rab7 GTPase were isolated and used to analyze the role of a rab7-regulated pathway in lysosome biogenesis. Expression of mutant rab7N125I protein induced a dramatic redistribution of cation-independent mannose 6–phosphate receptor (CI-MPR) from its normal perinuclear localization to large peripheral endosomes. Under these circumstances ∼50% of the total receptor and several lysosomal hydrolases cofractionated with light membranes containing early endosome and Golgi markers. Late endosomes and lysosomes were contained exclusively in well-separated, denser gradient fractions. Newly synthesized CI-MPR and cathepsin D were shown to traverse through an early endocytic compartment, and functional rab7 was crucial for delivery to later compartments. This observation was evidenced by the fact that 2 h after synthesis, both markers were more prevalent in fractions containing light membranes. In addition, both were sensitive to HRP-DAB– mediated cross-linking of early endosomal proteins, and the late endosomal processing of cathepsin D was impaired. Using similar criteria, the lysosomal membrane glycoprotein 120 was not found accumulated in an early endocytic compartment. The data are indicative of a post-Golgi divergence in the routes followed by different lysosome-directed molecules.

CD8+ T lymphocytes induce polarized exocytosis of secretory lysosomes by dendritic cells with release of interleukin-1β and cathepsin D

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2152-2159 ◽  
Author(s):  
Stefania Gardella ◽  
Cristina Andrei ◽  
Lavinia Vittoria Lotti ◽  
Alessandro Poggi ◽  
M. Rosaria Torrisi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocytes ◽  
Cathepsin D ◽  
Specific Interaction ◽  
Secretory Protein ◽  
Interleukin 1Β ◽  
Cd8 T Lymphocytes ◽  
Human Dendritic Cells ◽  
Secretory Lysosomes ◽  
Polarized Exocytosis

We recently reported that human dendritic cells release the leaderless secretory protein interleukin-1β (IL-1β) following specific interaction with alloreactive T lymphocytes. To clarify the molecular mechanism underlying this secretion, this study investigated the intracellular trafficking of IL-1β in dendritic cells and the signal(s) regulating its release. Results show that a fraction of the intracellular IL-1β precursor colocalizes with the hydrolase cathepsin D in endolysosomes of dendritic cells; secretion of both proteins is elicited by stimuli that induce intracellular calcium increases. Alloreactive CD8+ T lymphocytes generate a Ca++ influx in dendritic cells followed by enrichment in endolysosomes containing IL-1β and cathepsin D beneath the membrane in contact with T cells. These events result in polarized exocytosis of secretory lysosomes, mediated by microtubules, with release of IL-1β and cathepsin D toward the interacting CD8+ T cell.

β-Amyloid induces increased release of interleukin-1β from lipopolysaccharide-activated human monocytes

1996 ◽  
Vol 67 (1) ◽  
pp. 21-29 ◽  
Author(s):  
Dianne Lorton ◽  
June-Marie Kocsis ◽  
Lynda King ◽  
Kelly Madden ◽  
Kurt R. Brunden
Keyword(s):  
Interleukin 1Β ◽  
Human Monocytes ◽  
Β Amyloid

Recombinant human C5a induces transcription but not translation of interleukin-1β mRNA in human monocytes

1992 ◽  
Vol 143 (1) ◽  
pp. 117-123 ◽  
Author(s):  
T. Geiger ◽  
C. Rordorf ◽  
N. Galakatos ◽  
B. Seligmann ◽  
R. Henn ◽  
...  
Keyword(s):  
Interleukin 1Β ◽  
Human Monocytes

scholarly journals A fast-acting elastase inhibitor in human monocytes.

1985 ◽  
Vol 162 (6) ◽  
pp. 2142-2155 ◽  
Author(s):  
E Remold-O'Donnell
Keyword(s):  
Proteinase Inhibitor ◽  
Sodium Dodecyl ◽  
Human Monocyte ◽  
Sulfate Solution ◽  
Cell Protein ◽  
Human Monocytes ◽  
High Concentration ◽  
Elastase Inhibitor ◽  
Nucleophilic Cleavage ◽  
Fast Acting

A proteinase inhibitor active against neutrophil and pancreatic elastase was detected in extracts of cultured human monocytes and the human monocyte-like cell line U937. This component forms a covalent complex with the active site of elastase; the complex is stable in boiling sodium dodecyl sulfate solution, and is susceptible to nucleophilic cleavage. The activity of the elastase inhibitor is not detected in extracts of freshly isolated monocytes, but becomes detectable when the monocytes are allowed to mature in culture, with maximum levels occurring at 5-7 d. The monocyte inhibitor is fast-acting; its reaction with 125I-labeled elastase is complete in less than 1 min at 37 degrees C. Analysis by electrophoresis and studies using a heteroantiserum to alpha 1-proteinase inhibitor demonstrated that the elastase inhibitor of monocytes/U937 cells is not identical to alpha 1-proteinase inhibitor, the major elastase inhibitor of blood plasma. The extent of conversion of 125I-elastase to the 125I-elastase-inhibitor complex is proportional to the amount of U937 extract or cultured monocyte extract, indicating that this reaction can serve to quantify the elastase inhibitor. The elastase inhibitor is an abundant component in mature monocytes, with greater than or equal to 1.5 X 10(6) molecules/cell (greater than or equal to 12 micrograms per 10(8) cells, greater than 0.1% of total cell protein). Its mol wt is estimated at 50,000. Thus, the monocyte inhibitor should be classified as a putative regulator of neutrophil (and monocyte) elastase activity at inflammatory sites. This designation is based on the properties of the molecule, including its high concentration in maturing monocytes, its affinity for elastase, and its fast reaction with this enzyme.

scholarly journals WASH is required for lysosomal recycling and efficient autophagic and phagocytic digestion

2013 ◽  
Vol 24 (17) ◽  
pp. 2714-2726 ◽  
Author(s):  
Jason S. King ◽  
Aurélie Gueho ◽  
Monica Hagedorn ◽  
Navin Gopaldass ◽  
Florence Leuba ◽  
...  
Keyword(s):  
Cathepsin D ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Endosomal Sorting ◽  
Lipid Catabolism ◽  
Multilamellar Bodies ◽  
Important Regulator ◽  
Intracellular Vesicles ◽  
Syndrome Protein

Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) is an important regulator of vesicle trafficking. By generating actin on the surface of intracellular vesicles, WASH is able to directly regulate endosomal sorting and maturation. We report that, in Dictyostelium, WASH is also required for the lysosomal digestion of both phagocytic and autophagic cargo. Consequently, Dictyostelium cells lacking WASH are unable to grow on many bacteria or to digest their own cytoplasm to survive starvation. WASH is required for efficient phagosomal proteolysis, and proteomic analysis demonstrates that this is due to reduced delivery of lysosomal hydrolases. Both protease and lipase delivery are disrupted, and lipid catabolism is also perturbed. Starvation-induced autophagy therefore leads to phospholipid accumulation within WASH-null lysosomes. This causes the formation of multilamellar bodies typical of many lysosomal storage diseases. Mechanistically, we show that, in cells lacking WASH, cathepsin D becomes trapped in a late endosomal compartment, unable to be recycled to nascent phagosomes and autophagosomes. WASH is therefore required for the maturation of lysosomes to a stage at which hydrolases can be retrieved and reused.

scholarly journals Defects in Mitochondrial Clearance Predispose Human Monocytes to Interleukin-1β Hypersecretion

2013 ◽  
Vol 289 (8) ◽  
pp. 5000-5012 ◽  
Author(s):  
Robert van der Burgh ◽  
Lotte Nijhuis ◽  
Kalliopi Pervolaraki ◽  
Ewoud B. Compeer ◽  
Lieneke H. Jongeneel ◽  
...  
Keyword(s):  
Interleukin 1Β ◽  
Human Monocytes

Endocytosis of Proteins by Salivary Gland Duct Cells

1987 ◽  
Vol 66 (2) ◽  
pp. 412-419 ◽  
Author(s):  
A.R. Hand ◽  
R. Coleman ◽  
M.R. Mazariegos ◽  
J. Lustmann ◽  
L.V. Lotti
Keyword(s):  
Protein A ◽  
Periodate Oxidation ◽  
Secretory Protein ◽  
Secretory Proteins ◽  
Cationized Ferritin ◽  
Cell Secretion ◽  
High Concentration ◽  
Thin Sections ◽  
Duct Cells ◽  
Rat Parotid

The ability of the intralobular duct cells of the rat parotid gland to take up protein from the lumen was examined by retrograde infusion of exogenous proteins and by immunogold localization of endogenous secretory proteins. Small amounts of native horseradish peroxidase (HRP) were taken up by intercalated and striated duct cells, and were present in small vesicles, multi vesicular bodies, and lysosomes. In contrast, HRP modified by periodate oxidation was avidly internalized by the duct cells and was present in large apical vacuoles that acquired lysosomal hydrolase activity. Native and cationized ferritin were taken up in a similar manner when infused at a high concentration (up to 10 mg/mL). At lower concentrations (0.3-1.0 mg/mL), endocytosis of cationized ferritin occurred mainly in small apical tubules and vesicles in striated duct cells. Little native ferritin was taken up at these concentrations. After stimulation of acinar cell secretion by isoproterenol, similar vacuoles were occasionally observed in both intercalated and striated duct cells. Labeling of thin sections with antibodies to amylase and to a 26,000-dalton secretory protein (protein B1), followed by protein A-gold, revealed the presence of these proteins in the vacuoles, indicating endocytosis of acinar secretory proteins by the duct cells. Although uptake of acinar proteins by duct cells occurs at a low rate in normal animals, previous work suggests that extensive endocytosis may occur in certain pathological conditions. This may be a mechanism for removing abnormal or modified proteins from saliva before it reaches the oral cavity.

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