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Kinetics of Membrane Internalization and Recycling During Proc. Nati. Acad. Sci. USA Vol. 77, No. 2, pp. 1015-1019, February 1980 Cell Biology Kinetics of membrane internalization and recycling during pinocytosis in Dictyostelium discoideum (plasma membrane marker/pinosomal membrane/primary pinosome size/membrane shuttle) LUTZ THILO AND GUNTER VOGEL Max-Planck-Institut fur Biologie, 74 Tubingen, Federal Republic of Germany Communicated by George E. Palade, November 13,1979 ABSTRACT Internalization and recycling of plasma membrane internalization, the antibodies appeared in the membrane during pinocytosis in Dictyostelium discoideum was vacuolar system of the cells, and the antibody complex was analyzed quantitatively. A labeling technique was used by which [3Hlgalactose could be enzymaticallybound to and re- shown by isopycnic centrifugation to become associated with leased from the plasma membrane. Label internalized with the plasma membrane to which it had been recycled. Despite the plasma membrane was no longer accessible to enzymatic re- elegance of this method, it gave only qualitative evidence for lease and could therefore be distinguished quantitatively from membrane recycling. label remaining on the cell surface. Internalization of labeled An approach for analyzing internalization and recycling of membrane components was measured as a function of pinocy- totic uptake. Direct experimental evidence for membrane re- membrane is presented in this study. It is based on a labeling cycling was obtained by demonstrating that previously inter- system by which a radioactive marker can be. enzymatically nalized label reappeared at the plasma membrane. The exper- bound to and released from the plasma membrane. Label on imental data agree with a kinetic model requiring that a shuttle internalized membrane is no longer accessible to enzymatic of membrane between two membrane compartments leads to release and, therefore, can be quantitatively distinguished from the same surface concentration of label in both. The two com- label on the cell surface. We have used this technique to partments consist of the plasma membrane and of cytoplasmic study vacuolar membranes; their relative membrane surface areas are the flow of membrane during pinocytosis in Dictyostelium 1 and 0.5, respectively. One surface area equivalent of the discoideum, which depends on endocytosis as the sole mecha- plasma membrane is internalized during a pinocytotic uptake nism of food uptake. amounting to 15% of the cell volume. At the observed rate of pinocytosis, this occurred once every 45 min. The average size of the primary pinosomes, as weighted according to their con- MATERIALS AND METHODS tribution to pinocytotic uptake, was calculated to be about 0.6 Culture Conditions. D. discoideum strain AX2 (ATCC Am. 24397) was grown axenically at 20°C as described (17). Cells Endocytosis is performed by a large variety of eukaryotic cells were harvested at a density of 2 X 106 cells per ml by centri- (1-5). During endocytosis, the plasma membrane invaginates fuging at 100 X g for 5 min and were washed in cold phosphate and encloses extracellular fluid (pinocytosis) or particles buffer (20 mM potassium phosphate, pH 6.5). Cell density was (phagocytosis) in plasma-membrane-derived vesicles. This determined with a particle counter (Coulter model DN). process leads to an extensive internalization of plasma mem- Pinocytosis Assay. Fluorescein-labeled dextran (FITC- brane varying between 1 and 20 times the total cell surface area dextran 40, Pharmacia) is a suitable fluid phase marker for per hr, depending on cell type and culture conditions (6-12). measuring pinocytotic fluid uptake (unpublished data). Uptake However, during endocytosis no reduction of the cell surface of FITC-dextran is directly proportional to its concentration area is observed. This implies that internalized membrane is in the medium (0.5-10 mg/ml) and proceeds linearly with time replaced at a corresponding rate. De novo membrane synthesis for at least 1 hr at 200C. The measured uptake rates were is too slow to account for membrane replacement, considering identical to those measured with the use of horseradish perox- the long lifetime of membrane components, on the order of idase, a well-established fluid phase marker (18). Cells were 10-100 hr (3, 5, 13). Therefore, it is generally assumed that suspended at a density of 5 X 106 cells per ml in axenic medium, internalized membrane is recycled to the plasma membrane, and FITC-dextran was added to a final concentration of 2 as was initially proposed as a result of electron microscopic mg/ml. Cells were incubated at the appropriate temperature observation (14, 15). on a rotary shaker (100 rpm). Samples of 1 ml were diluted 1:5 The methods used to demonstrate membrane internalization into ice-cold phosphate buffer to stop pinocytosis. Cells were were mostly based on electron microscopic morphological ob- collected by centrifugation at 100 X g for 5 min and resus- servations identifying endocytosis-derived internal membrane pended in 1 ml of phosphate buffer. For complete removal of structures. Because these methods used either endocytotic external FITC-dextran, the cell suspension was layered over content markers or noncovalently linked markers to unspecified and centrifuged through (200 X g, 10 min) an aqueous solution membrane components, previous results were difficult to (10 ml, 7 cm height) of 20% (wt/wt) poly(ethyleneglycol) 6000 quantify. For the same reason these methods were not suitable (Serva). Cells were washed and resuspended in 2 ml of 50 mM for yielding direct evidence for membrane recycling. The first Na2HPO4, pH 9.3. After the cells were counted, they were lysed such evidence was reported by Schneider et al. (16) for cultured with 0.1% Triton X-100 and fluorescence intensity was deter- fibroblasts: After the consecutive uptake of fluorescein-labeled mined (excitation wavelength 470 nm, emission wavelength anti-IgG by pinocytosis and anti-plasma membrane IgG by 520 nm). The pinocytosed volume was determined by com- parison with a standard curve. The publication costs of this article were defrayed in part by page Isolation of Total Membrane. Cells in phosphate buffer (108 charge payment. This article must therefore be hereby marked "ad- cells per ml) were disrupted by freezing and thawing, diluted vertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. Abbreviation: FITC-dextran, fluorescein-labeled dextran. 1015 Downloaded by guest on September 26, 2021 1016 Cell Biology: Thilo and Vogel Proc. Natl. Acad. Sci. USA 77 (1980) 1:10 in phosphate buffer, and gently sonicated in a water bath Time of incubation with galactosyltransferase, min for about 30 sec at 0C. Unbroken cells (<1%) and nuclei were I 0 20 40 60 80 removed by centrifugation at 5000 rpm for 5 min. Total i c 10 membrane was isolated from the supernatant by centrifugation at 105Xgfor60minat40C. 0 0 0 Polyacrylamide Gel Electrophoresis. Membrane proteins 8 -U were dissociated by heating at 1000C for 3 min in a solution -6 containing 1% NaDodSO4 and 0.1 M 2-mercaptoethanol. U .o0 0 Electrophoresis was performed in gradient slab gels (7-20% 0 +1 polyacrylamide, 0.1% NaDodSO4) with a discontinuous buffer V 4u c E system (19). Protein bands were stained with Coomassie brilliant :3 blue. The gels were sliced at 1-mm intervals; the fractions were 0 0Oa dissolved in Protosol (New England Nuclear) for 2 hr at 7jD u 4 0co 0C 600C. 4- ._.0 c Cell Dimensions. Cells were fixed in culture by the addition :3 of 2% glutaraldehyde for 30 min at 200C. The average cell di- 2 D0 ameter was measured by light microscopy. The circumference z of electronmicroscopically observed cell cross sections was IL J0 determined to be about 2.2 times that of a circle enclosing the 101 - IX-x--X----x--------x same cross-sectional area. The surface-to-volume ratio of the II 0 2 4 6 8 cells was therefore taken as (2.2)2 - 5 times that of a sphere. 10 2o24 Reversible Labeling of Plasma Membrane. [3H]Galactose Time of incubation with 3-galactosidase, hr was covalently linked to terminal N-acetylglucosamine moieties FIG. 1. Kinetics of enzymatic binding and release of [3H]Gal. The on the cell surface of D. discoideum (20-22) with galactosyl- amount of [3H]Gal bound to the cell surface is shown as a function of transferase (EC 2.4.1.22) (23, 24) from bovine milk (Sigma) incubation time in the presence (0) and absence (X) of galactosyl- transferase. Labeled cells (2 min at 0C) were incubated with f3-gal- according to the reaction: actosidase. The fraction of [3H]Gal remaining bound to the cell surface is shown as a function of time: at 20'C for cells fixed with glutaral- UDPGal + GlcNAc -- UDP + N-acetyllactosamine. dehyde (0) and at 0C for unfixed cells (3). Error bars, SEM (about For labeling, cells were resuspended at 00C to a density of about 4 values). 108 cells per ml in phosphate buffer containing 10 mM MnCl2, 2.2 kiM UDP[6-3H]Gal (ammonium salt, 18.5 Ci/mmol, Am- amount of [3H]Gal accessible to /-galactosidase was determined ersham; 1 Ci = 3.7 X 1010 becquerels), and galactosyltransferase by incubating fixed cells with the enzyme for about 8-10 hr at (0.5 unit/ml) was added. The reaction was stopped by 1:10 200C. dilution in ice-cold phosphate buffer, and cells were immedi- ately washed in the same volume until no radioactivity was RESULTS found in the supernatant (about four times). Kinetics of binding Cells were labeled at 0C to prevent internalization of label under these conditions are shown in Fig. 1. During this study, during the labeling procedure (see below). Immediately after labeling was performed at 0°C for 2 min. About 106 molecules labeling, the cells were resuspended in axenic medium and of [3H]Gal were bound per cell under the chosen conditions, divided into two portions, to one of which FITC-dextran was which yielded adequate experimental sensitivity.
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