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  • 1. Ambort, D.
    et al.
    Johansson, M.E.V.
    Gustafsson, J. K.
    Nilsson, Harriet
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology.
    Ermund, A.
    Johansson, B.R.
    Koeck, Philip J. B.
    KTH, School of Technology and Health (STH), Structural Biotechnology (Closed 20130701).
    Hebert, Hans
    KTH, School of Technology and Health (STH), Structural Biotechnology (Closed 20130701).
    Hansson, G.C.
    Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 15, p. 5645-5650Article in journal (Refereed)
    Abstract [en]

    MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca2+ it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. TheMUC2-N aggregates were dissolved by removing Ca2+ and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.

  • 2. Braniste, Viorica
    et al.
    Al-Asmakh, Maha
    Kowal, Czeslawa
    Anuar, Farhana
    Abbaspour, Afrouz
    Toth, Miklos
    Korecka, Agata
    Bakocevic, Nadja
    Guan, Ng Lai
    Kundu, Parag
    Gulyas, Balazs
    Halldin, Christer
    Hultenby, Kjell
    Nilsson, Harriet
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Hebert, Hans
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Volpe, Bruce T.
    Diamond, Betty
    Pettersson, Sven
    The gut microbiota influences blood-brain barrier permeability in mice2014In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 6, no 263, p. 263ra158-Article in journal (Refereed)
    Abstract [en]

    Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.

  • 3. Chen, Gefei
    et al.
    Abelein, Axel
    Nilsson, Harriet E.
    KTH, School of Technology and Health (STH), Medical Engineering, Structural Biotechnology.
    Leppert, Axel
    Andrade-Talavera, Yuniesky
    Tambaro, Simone
    Hemmingsson, Lovisa
    Roshan, Firoz
    Landreh, Michael
    Biverstal, Henrik
    Koeck, Philip J. B.
    KTH, School of Technology and Health (STH), Medical Engineering, Structural Biotechnology.
    Presto, Jenny
    Hebert, Hans
    Fisahn, Andre
    Johansson, Jan
    Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 2081Article in journal (Refereed)
    Abstract [en]

    . Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer's disease the amyloid-beta peptide (A beta) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces A beta fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible nonfibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of A beta, while dimers strongly suppress A beta fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity.

  • 4. Ermund, Anna
    et al.
    Meiss, Lauren N.
    Rodriguez-Pineiro, Ana M.
    Baehr, Andrea
    Nilsson, Harriet E.
    KTH, School of Technology and Health (STH), Medical Engineering. Department of Medical Biochemistry, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Department of Biosciences and Nutrition, Karolinska Institutet, and School of Technology and Health, KTH Royal Institute of Technology, Novum, SE-141 57 Huddinge, Sweden.
    Trillo-Muyo, Sergio
    Ridley, Caroline
    Thornton, David J.
    Wine, Jeffrey J.
    Hebert, Hans
    KTH, School of Technology and Health (STH), Medical Engineering, Structural Biotechnology. Department of Biosciences and Nutrition, Karolinska Institutet, and School of Technology and Health, KTH Royal Institute of Technology, Novum, SE-141 57 Huddinge, Sweden.
    Klymiuk, Nikolai
    Hansson, Gunnar C.
    The normal trachea is cleaned by MUC5B mucin bundles from the submucosal glands coated with the MUC5AC mucin2017In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 492, no 3, p. 331-337Article in journal (Refereed)
    Abstract [en]

    To understand the mucociliary clearance system, mucins were visualized by light, confocal and electron microscopy, and mucus was stained by Alcian blue and tracked by video microscopy on tracheal explants of newborn piglets. We observed long linear mucus bundles that appeared at the submucosal gland openings and were transported cephalically. The mucus bundles were shown by mass spectrometry and immunostaining to have a core made of MUC5B mucin and were coated with MUC5AC mucin produced by surface goblet cells. The transport speed of the bundles was slower than the airway surface liquid flow. We suggest that the goblet cell MUC5AC mucin anchors the mucus bundles and thus controls their transport. Normal clearance of the respiratory tree of pigs and humans, both rich in submucosal glands, is performed by thick and long mucus bundles. 

  • 5. Gustafsson, JK
    et al.
    Ermund, Anna
    Ambort, Daniel
    Johansson, MEV
    Nilsson, Harriet
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology.
    Thorell, K
    Hebert, Hans
    Karolinska Institutet, Sweden .
    Sjövall, H
    Hansson, Gunnar
    Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype2012In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 209, no 7, p. 1263-1272Article in journal (Refereed)
    Abstract [en]

    Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrΔ508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF.

  • 6. Kozlova, Inna
    et al.
    Nilsson, Harriet
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology.
    Henriksnäs, Johanna
    Roomans, Godfried M
    X-ray microanalysis of apical fluid in cystic fibrosis airway epithelial cell lines.2006In: Cellular Physiology and Biochemistry, ISSN 1015-8987, E-ISSN 1421-9778, Vol. 17, no 1-2, p. 13-20Article in journal (Refereed)
    Abstract [en]

    The ionic composition of the fluid lining the airways (airway surface liquid, ASL) in healthy subjects and patients with cystic fibrosis (CF) has been a matter of controversy. It has been attempted to resolve conflicting theories by using cell cultures, but published results show a wide variety of values for the ionic concentrations in the apical fluid in these cultures. To investigate CFTR-mediated HCO(3)(-) conductance and the role of HCO(3)(-) in regulating ASL pH we determined the pH of the fluid covering the apical surface of airway epithelial cells. A normal (16HBE14o (-)) and a CF (CFBE41o (-)) bronchial epithelial cell line were grown on membrane inserts in both a liquid-liquid interface culture system for 7 days, and in an air-liquid interface culture system for one month. The elemental composition of the fluid covering the apical surface was determined by X-ray microanalysis of frozen-hydrated specimens, or by X-ray microanalysis of Sephadex beads that had been equilibrated with the apical fluid. Analysis showed that the apical fluid had a Na(+) and Cl(-) concentration of about 80-100 mM and thus was slightly hypotonic. The ionic concentrations were somewhat higher in air-liquid interface than in liquid-liquid interface cultures. The apical fluid in CF cells had significantly higher concentrations of Na and Cl than that in control cultures. In control cultures, the concentrations of Na and Cl in the apical fluid increased if glibenclamide, an inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR) was added to the apical medium. Exposing the cells to the metabolic inhibitor NaCN also resulted in a significant increase of the Na and Cl concentrations in the apical fluid. The results agree with the notion that these cell cultures are mainly absorptive cells, and that ion absorption by the CF cells is reduced compared to that in normal cells. The pH measurements of the fluid covering the apical part of cell cultures support the notion that bicarbonate ions may be transported by CFTR, and that this can be inhibited by specific CFTR inhibitors.

  • 7. Kozlova, Inna
    et al.
    Nilsson, Harriet
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology.
    Phillipson, Mia
    Riederer, Brigitte
    Seidler, Ursula
    Colledge, William H
    Roomans, Godfried M
    X-ray microanalysis of airway surface liquid in the mouse.2005In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 288, no 5, p. L874-8Article in journal (Refereed)
    Abstract [en]

    The ionic composition of airway surface liquid (ASL) has been debated, and, in particular for the mouse, a wide range of values has been published. Two techniques were developed to measure the elemental composition of the ASL. X-ray microanalysis of ASL was carried out at low temperature on trachea removed from isoflurane-anesthetized animals and shock-frozen. In the second technique, dextran beads were placed on top of the epithelium of the trachea removed from pentobarbital-anesthetized animals, left to equilibrate with the ASL, dried, and subjected to X-ray microanalysis. Both techniques showed that mouse tracheal ASL has significantly lower concentrations of Na and Cl (approximately 60-80 mM) than serum. Differences between the two techniques were due to different sampling of mucus. CFTR(-/-) mice had significantly higher concentrations of Na and Cl in their ASL than age-matched controls. Pilocarpine or isoproterenol stimulation significantly reduced the ion concentrations in tracheal ASL. ASL was also collected with the dextran bead method from the nasal cavity in situ in pentobarbital-anesthetized animals. In control animals, the elemental composition of nasal fluid was similar to that of tracheal ASL. Pilocarpine stimulation caused a significant increase in Na, Cl, and K; stimulation with isoproterenol or phenylephrine caused a significant increase only in K. It is concluded that mouse ASL under unstimulated conditions is hypotonic, which may be related to the relative paucity of submucosal glands in the mouse trachea.

  • 8.
    Nilsson, Harriet
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology.
    Dragomir, Anca
    Ahlander, Anders
    Johannesson, Marie
    Roomans, Godfried M
    Effects of hyperosmotic stress on cultured airway epithelial cells.2007In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 330, no 2, p. 257-69Article in journal (Refereed)
    Abstract [en]

    Inhalation of hyperosmotic solutions (salt, mannitol) has been used in the treatment of patients with cystic fibrosis or asthma, but the mechanism behind the effect of hyperosmotic solutions is unclear. The relation between osmolarity and permeability changes was examined in an airway cell line by the addition of NaCl, NaBr, LiCl, mannitol, or xylitol (295-700 mOsm). Transepithelial resistance was measured as an indicator of the tightness of the cultures. Cell-cell contacts and morphology were investigated by immunofluorescence and by transmission electron microscopy, with lanthanum nitrate added to the luminal side of the epithelium to investigate tight junction permeability. The electrolyte solutions caused a significant decrease in transepithelial resistance from 450 mOsm upwards, when the hyperosmolar exposure was gradually increased from 295 to 700 mOsm; whereas the nonelectrolyte solutions caused a decrease in transepithelial resistance from 700 mOsm upwards. Old cultures reacted in a more rigid way compared to young cultures. Immuno-fluorescence pictures showed weaker staining for the proteins ZO-1, claudin-4, and plakoglobin in treated samples compared to the control. The ultrastructure revealed an increased number of open tight junctions as well as a disturbed morphology with increasing osmolarity, and electrolyte solutions opened a larger proportion of tight junctions than nonelectrolyte solutions. This study shows that hyperosmotic solutions cause the opening of tight junctions, which may increase the permeability of the paracellular pathway and result in increased transepithelial water transport.

  • 9. Nilsson, Harriet
    et al.
    Dragomir, Anca
    Ahlander, Anders
    Ljungkvist, Marianne
    Roomans, Godfried M
    A modified technique for the impregnation of lanthanum tracer to study the integrity of tight junctions on cells grown on a permeable substrate.2006In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 69, no 10, p. 776-83Article in journal (Refereed)
    Abstract [en]

    Ionic lanthanum is commonly used to trace permeability pathways across epithelia and endothelia in biological electron microscopy. A method for obtaining a uniformly dense precipitate of lanthanum is described. The method, which is a modification of the technique described by Shaklai and Tavassoli (1977) was suitable for fixation of cell cultures grown on permeable filter inserts and was successfully applied to study opening of tight junctions by hypertonic solutions in the airway epithelial cell line 16HBE14o(-). The preparation method formed the basis for a semiquantitative morphological determination in which the tight junctions were subdivided as "intact," "weakened," and "open." By using this modified technique, it could be demonstrated that opening of tight junctions in airway epithelial cells increased, with increasing osmolarity with electrolytes having a stronger effect than nonelectrolytes. A significant linear relationship was found between the osmolarity of the medium and the open state of the tight junctions (as determined by the semiquantitative morphological technique) or the transepithelial electrical resistance.

  • 10. Nilsson, Harriet
    et al.
    Dragomir, Anca
    Lazorova, Lucia
    Johannesson, Marie
    Roomans, Godfried M
    CFTR and tight junctions in cultured bronchial epithelial cells.2010In: Experimental and molecular pathology (Print), ISSN 0014-4800, E-ISSN 1096-0945, Vol. 88, no 1, p. 118-27Article in journal (Refereed)
    Abstract [en]

    Airway epithelial salt and water transport takes place through paracellular and transcellular pathways. This transport depends critically on the epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane conductance regulator (CFTR), operating in concert with the paracellular pathway through the tight junctions (TJ). Normal (16HBE14o-), cystic fibrosis (CFBE41o-), and corrected CFBE41o- (CFBE41o-pCep4 overexpressing wtCFTR) airway epithelial cell lines were cultured under isotonic conditions. Transepithelial electrical resistance (TEER) was measured as indicator of the tightness of the cultures. Morphology was investigated by immunofluorescence and paracellular permeability by lanthanum nitrate or [14C] mannitol as permeability markers. The CFTR-defective cell line CFBE41o- developed higher TEER than its corrected counterpart CFBE41o-pCep4. Addition of a specific inhibitor of CFTR (CFTR(inh)-172) to 16HBE14o- and CFBE41o-pCep4 cells resulted in a time-dependent increase in TEER, whereas stimulation of CFTR by IBMX and forskolin caused a decrease. Permeability to lanthanum and [14C] mannitol was lower in CFBE41o- and in 16HBE14o- cells exposed to CFTR(inh)-172, compared to untreated 16HBE14o- and CFBE41o-pCep4 cells, respectively. 16HBE14o- cells exposed to IBMX and forskolin showed higher permeability to lanthanum but lower permeability to [14C] mannitol compared to control. Immunofluorescence revealed a disorganization of F-actin and alpha-tubulin in 16HBE14o- cells and CFBE41o- pCep4 exposed to CFTR(inh)-172 and in CFBE41o- cells. Changes in F-actin and alpha-tubulin in 16HBE14o- cells exposed to IBMX and forskolin were also seen. These results suggest the possibility of an interaction between CFTR and the TJ protein complex, probably via the cytoskeleton.

  • 11.
    Nilsson, Harriet E.
    et al.
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Ambort, Daniel
    Bäckström, Malin
    Thomsson, Elisabeth
    Koeck, Philip J. B.
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology. Department of Biosciences and Nutrition, Karolinska Institutet.
    Hansson, Gunnar C.
    Hebert, Hans
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology. epartment of Biosciences and Nutrition, Karolinska Institutet.
    Intestinal MUC2 Mucin Supramolecular Topology by Packing and Release Resting on D3 Domain Assembly2014In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 426, no 14, p. 2567-2579Article in journal (Refereed)
    Abstract [en]

    MUC2 is the major gel-forming mucin of the colon forming a protective gel barrier organized into an inner stratified and an outer loose layer. The MUC2 N-terminus (D1-D2-D'D3 domains) has a dual function in building a net-like structure by disulfide-bonded trimerization and packing the MUC2 polymer into an N-terminal concatenated polygonal platform with the C-termini extending perpendicularly by pH- and calcium-dependent interactions. We studied the N-terminal D'D3 domain by producing three recombinant variants, with or without Myc tag and GFP (green fluorescent protein), and analyzed these by gel filtration, electron microscopy and single particle image processing. The three variants were all trimers when analyzed upon denaturing conditions but eluted as hexanners upon gel filtration under native conditions. Studies by electron microscopy and three-dimensional maps revealed cage-like structures with 2- and 3-fold symmetries. The structure of the MUC2 D3 domain confirms that the MUC2 mucin forms branched net-like structures. This suggests that the MUC2 mucin is stored with two N-terminal concatenated ring platforms turned by 180 against each other, implicating that every second unfolded MUC2 net in mature mucus is turned upside down.

  • 12. Nilsson, Harriet
    et al.
    Kozlova, Inna
    Vanthanouvong, Viengphet
    Roomans, Godfried M
    Collection and X-ray microanalysis of airway surface liquid in the mouse using ion exchange beads.2004In: Micron, ISSN 0968-4328, E-ISSN 1878-4291, Vol. 35, no 8, p. 701-5Article in journal (Refereed)
    Abstract [en]

    The airway surface liquid (ASL) is a thin layer of liquid covering the airway epithelium. The ionic composition of the ASL is assumed to be important for airway function and may be altered in diseases such as cystic fibrosis and exercise-induced asthma. A method for collection of ASL is presented in which the fluid is collected using small dextran ion-exchange beads. The beads are equilibrated with the ASL in a humidity chamber, collected under silicon oil, dried and analyzed by X-ray microanalysis. Analysis of standard beads prepared by exposure to different salt solutions shows that linear calibration lines can be obtained, but that beads absorb different elements to a different extent. The results show that the ASL in mice is hypotonic, and that the mucus component of the ASL has an elemental composition that is different from that of the periciliary fluid.

  • 13. Roomans, Godfried M
    et al.
    Kozlova, Inna
    Nilsson, Harriet
    Vanthanouvong, Viengphet
    Button, Brian
    Tarran, Robert
    Measurements of airway surface liquid height and mucus transport by fluorescence microscopy, and of ion composition by X-ray microanalysis.2004In: Journal of Cystic Fibrosis, ISSN 1569-1993, E-ISSN 1873-5010, Vol. 3 Suppl 2, p. 135-9Article in journal (Refereed)
    Abstract [en]

    The respiratory tract is lined by a thin layer of fluid, the airway surface liquid (ASL), which plays a critical role in lung defense. The paper describes methods to determine the height of the ASL and corresponding mucus transport rates using fluorescent probes, and methods to determine the ionic composition of the ASL by X-ray microanalysis.

  • 14.
    Trillo-Muyo, Sergio
    et al.
    Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
    Nilsson, Harriet E.
    KTH, School of Technology and Health (STH). Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden.;Karolinska Inst, Dept Biosci & Nutr, S-14157 Huddinge, Sweden.
    Recktenwald, Christian V.
    Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
    Ermund, Anna
    Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
    Ridley, Caroline
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Wellcome Trust Ctr Cell Matrix Res, Fac Biol Med & Hlth, Manchester M13 9PT, Lancs, England..
    Meiss, Lauren N.
    Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
    Baehr, Andrea
    Ludwig Maximilians Univ Munchen, Inst Mol Anim Breeding & Biotechnol, Gene Ctr, Hackerstr 27, D-85764 Oberschleissheim, Germany..
    Klymiuk, Nikolai
    Ludwig Maximilians Univ Munchen, Inst Mol Anim Breeding & Biotechnol, Gene Ctr, Hackerstr 27, D-85764 Oberschleissheim, Germany..
    Wine, Jeffrey J.
    Stanford Univ, Cyst Fibrosis Res Lab, Stanford, CA 94305 USA..
    Köck, Philip J. B.
    KTH, School of Technology and Health (STH). Karolinska Inst, Dept Biosci & Nutr, S-14157 Huddinge, Sweden.
    Thornton, David J.
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Wellcome Trust Ctr Cell Matrix Res, Fac Biol Med & Hlth, Manchester M13 9PT, Lancs, England..
    Hebert, Hans
    Karolinska Inst, Dept Biosci & Nutr, S-14157 Huddinge, Sweden.;KTH Royal Inst Technol, Sch Technol & Hlth, S-14157 Huddinge, Sweden..
    Hansson, Gunnar C.
    Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
    Granule-stored MUC5B mucins are packed by the non-covalent formation of N-terminal head-to-head tetramers2018In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 15, p. 5746-5754Article in journal (Refereed)
    Abstract [en]

    Most MUC5B mucin polymers in the upper airways of humans and pigs are produced by submucosal glands. MUC5B forms N-terminal covalent dimers that are further packed into larger assemblies because of low pH and high Ca2+ in the secretory granule of the mucin-producing cell. We purified the recombinant MUC5B N-terminal covalent dimer and used single-particle electron microscopy to study its structure under intracellular conditions. We found that, at intragranular pH, the dimeric MUC5B organized into head-to-head noncovalent tetramers where the von Willebrand D1-D2 domains hooked into each other. These N-terminal tetramers further formed long linear complexes from which, we suggest, the mucin domains and their C termini project radially outwards. Using conventional and video microscopy, we observed that, upon secretion into the submucosal gland ducts, a flow of bicarbonate-rich fluid passes the mucin-secreting cells. We suggest that this unfolds and pulls out the MUC5B assemblies into long linear threads. These further assemble into thicker mucin bundles in the glandular ducts before emerging at the gland duct opening. We conclude that the combination of intracellular packing of the MUC5B mucin and the submucosal gland morphology creates an efficient machine for producing linear mucin bundles.

  • 15.
    Yan, Hongji
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Glycoscience.
    Chircov, Cristina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Glycoscience.
    Zhong, Xueying
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Winkeljann, Benjamin
    Tech Univ Munich, Dept Mech Engn, Boltzmannstr 11, D-85748 Garching, Germany.;Tech Univ Munich, Munich Sch Bioengn, Boltzmannstr 11, D-85748 Garching, Germany..
    Dobryden, Illia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Nilsson, Harriet Elisabeth
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden..
    Lieleg, Oliver
    Tech Univ Munich, Dept Mech Engn, Boltzmannstr 11, D-85748 Garching, Germany.;Tech Univ Munich, Munich Sch Bioengn, Boltzmannstr 11, D-85748 Garching, Germany..
    Claesson, Per M.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Hedberg, Yolanda
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Crouzier, Thomas
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Glycoscience.
    Reversible Condensation of Mucins into Nanoparticles2018In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 34, no 45, p. 13615-13625Article in journal (Refereed)
    Abstract [en]

    Mucins are high molar mass glycoproteins that assume an extended conformation and can assemble into mucus hydrogels that protect our mucosal epithelium. In nature, the challenging task of generating a mucus layer, several hundreds of micrometers in thickness, from micrometer-sized cells is elegantly solved by the condensation of mucins inside vesicles and their on-demand release from the cells where they suddenly expand to form the extracellular mucus hydrogel. We aimed to recreate and control the process of compaction for mucins, the first step toward a better understanding of the process and creating biomimetic in vivo delivery strategies of macromolecules. We found that by adding glycerol to the aqueous solvent, we could induce drastic condensation of purified mucin molecules, reducing their size by an order of magnitude down to tens of nanometers in diameter. The condensation effect of glycerol was fully reversible and could be further enhanced and partially stabilized by cationic cross-linkers such as calcium and polylysine. The change of structure of mucins from extended molecules to nano-sized particles in the presence of glycerol translated into macroscopic rheological changes, as illustrated by a dampened shear-thinning effect with increasing glycerol concentration. This work provides new insight into mucin condensation, which could lead to new delivery strategies mimicking cell release of macromolecules condensed in vesicles such as mucins and heparin.

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