The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system
Thaher Pelaseyed
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorJoakim H. Bergström
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorJenny K. Gustafsson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorAnna Ermund
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorGeorge M. H. Birchenough
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorAndré Schütte
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorSjoerd van der Post
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorFrida Svensson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorAna M. Rodríguez-Piñeiro
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorElisabeth E. L. Nyström
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorCatharina Wising
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorMalin E. V. Johansson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorCorresponding Author
Gunnar C. Hansson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Correspondence to:
Gunnar C. Hansson
Department of Medical Biochemistry
University of Gothenburg
Box 440, 405 30 Gothenburg, Sweden
Tel.: +46 31 786 3488
Fax: +46 31 416108
e-mail: [email protected]
Search for more papers by this authorThaher Pelaseyed
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorJoakim H. Bergström
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorJenny K. Gustafsson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorAnna Ermund
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorGeorge M. H. Birchenough
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorAndré Schütte
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorSjoerd van der Post
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorFrida Svensson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorAna M. Rodríguez-Piñeiro
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorElisabeth E. L. Nyström
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorCatharina Wising
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorMalin E. V. Johansson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorCorresponding Author
Gunnar C. Hansson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Correspondence to:
Gunnar C. Hansson
Department of Medical Biochemistry
University of Gothenburg
Box 440, 405 30 Gothenburg, Sweden
Tel.: +46 31 786 3488
Fax: +46 31 416108
e-mail: [email protected]
Search for more papers by this authorSummary
The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103+ type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
References
- 1Schade C, Flemstrom G, Holm L. Hydrogen ion concentration in the mucus layer on top of acid-stimulated and -inhibited rat gastric mucosa. Gastroenterology 1994; 107: 180–188.
- 2Johansson MEV, Phillipson M, Petersson J, Holm L, Velcich A, Hansson GC. The inner of the two Muc2 mucin dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA 2008; 105: 15064–15069.
- 3Gerbe F, et al. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J Cell Biol 2011; 192: 767–780.
- 4Vantourout P, Hayday A. Six-of-the-best: unique contributions of gd T cells to immunology. Nat Rev Immunol 2013; 13: 88–100.
- 5Gill N, Wlodarska M, Finlay BB. The future of mucosal immunology: studying an integrated system-wide organ. Nat Immunol 2010; 11: 558–560.
- 6Atuma C, Strugula V, Allen A, Holm L. The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol 2001; 280: G922–G929.
- 7Wilson FA, Dietschy JM. Characterization of bile acid absorption across the unstirred water layer and brush border of the rat jejunum. J Clin Invest 1972; 51: 3015–3025.
- 8Ermund A, Schutte A, Johansson MEV, Gustafsson JK, Hansson GC. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. Am J Physiol Gastrointest Liver Physiol 2013; 305: G341–G347.
- 9Puchtler H, Waldrop FS, Meloan SN, Terry MS, Conner HM. Methacarn (methanol-Carnoy) fixation. Practical and theoretical considerations. Histochemie 1970; 21: 97–116.
- 10Johansson MEV, Thomsson KA, Hansson GC. Proteomic analyses of the two mucus layers of the colon barrier reveal that their main component, the Muc2 Mucin, is strongly bound to the Fcgbp protein. J Proteome Res 2009; 8: 3549–3557.
- 11Rodriguez-Pineiro AM, et al. Studies of mucus in mouse stomach, small intestine, and colon. II. Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins. Am J Physiol Gastrointest Liver Physiol 2013; 305: G348–G356.
- 12Bhaskar KR, et al. Viscous fingering of HCl through gastric mucin. Nature 1992; 360: 458–461.
- 13Johansson M, Synnerstad I, Holm L. Acid transport through channels in the mucous layer of rat stomach. Gastroenterology 2000; 119: 1297–1304.
- 14Gruber AD, Elble RC, Ji HL, Schreur KD, Fuller CM, Pauli BU. Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl-channel proteins. Genomics 1998; 54: 200–214.
- 15Yurtsever Z, et al. Self-cleavage of human CLCA1 by a novel internal metalloprotease domain controls calcium-activated chloride channel activation. J Biol Chem 2012; 287: 42138–42149.
- 16Harada N, et al. Human IgGFc binding protein (Fcgamma BP) in colonic epithelial cells exhibits mucin-like structure. J Biol Chem 1997; 272: 15232–15241.
- 17Park SW, et al. The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci USA 2009; 106: 6950–6955.
- 18Bevins CL. Paneth cell defensins: key effector molecules of innate immunity. Biochem Soc Trans 2006; 34: 263–266.
- 19Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol 2010; 26: 547–553.
- 20Heazlewood CK, et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 2008; 5: e54.
- 21Renner M, et al. DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn's disease. Gastroenterology 2007; 133: 1499–1509.
- 22Vaishnava S, et al. The antibacterial lectin RegIIIg promotes the spatial segregation of microbiota and host in the intestine. Science 2011; 334: 255–258.
- 23Johansson MEV, Hansson GC. Microbiology. Keeping bacteria at a distance. Science 2011; 334: 182–183.
- 24Hornef MW, Wick MJ, Rhen M, Normark S. Bacterial strategies for overcoming host innate and adaptive immune responses. Nat Immunol 2002; 3: 1033–1040.
- 25Stecher B, Hapfelmeier S, Muller C, Kremer M, Stallmach T, Hardt WD. Flagella and chemotaxis are required for efficient induction of Salmonella enterica serovar Typhimurium colitis in streptomycin-pretreated mice. Infect Immun 2004; 72: 4138–4150.
- 26Newberry RD, Lorenz RG. Organizing a mucosal defense. Immunol Rev 2005; 206: 6–21.
- 27Neutra MR, Frey A, Kraehenbuhl JP. Epithelial M cells: gateways for mucosal infection and immunization. Cell 1996; 86: 345–348.
- 28Ermund A, Gustafsson JK, Hansson GC, Keita ÅA. Mucus properties and goblet cell quantification in mouse, rat, and human ileal Peyer's patches. PLoS ONE 2013; 8: e83688.
- 29Gustafsson JK, et al. Bicarbonate and functional CFTR channel is required for proper mucin secretion and link Cystic Fibrosis with its mucus phenotype. J Exp Med 2012; 209: 1263–1272.
- 30Johansson MEV. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS ONE 2012; 7: e41009.
- 31Ambort D, et al. Calcium and pH-dependent Packing and Release of the Gel-forming MUC2 Mucin. Proc Natl Acad Sci USA 2012; 109: 5645–5650.
- 32Specian D, Neutra MR. Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine. J Cell Biol 1980; 85: 626–640.
- 33Grootjans J, et al. Ischemia-induced mucus barrier loss and bacterial penetration are rapidly counteracted by increased goblet cell secretory activity in human and rat colon. Gut 2013; 62: 250–258.
- 34Johansson MEV, Hansson GC. The goblet cell: a key player in ischemia-reperfusion injury. Gut 2013; 62: 188–189.
- 35Johansson MEV, Sjovall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat Rev Gastroenterol Hepatol 2013; 10: 352–361.
- 36Johansson MEV, et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and in patients with ulcerative colitis. Gut 2014; 213: 281–291.
- 37Round AN, Rigby NM, Garcia de la Torre A, Macierzanka A, Mills ENC, Mackie AR. Lamellar structures of MUC2-rich mucin: a potential role in governing the barrier and lubricating functions of intestinal mucus. Biomacromolecules 2012; 13: 3253–3261.
- 38Johansson MEV, et al. Bacteria penetrate the inner mucus layer before inflammation in the Dextran sulfate colitis model. PLoS ONE 2010; 5: e12238.
- 39Van der Sluis M, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 2006; 131: 117–129.
- 40Velcich A, et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 2002; 295: 1726–1729.
- 41Johansson MEV, Holmen Larsson JM, Hansson GC. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc Natl Acad Sci USA 2011; 108: 4659–4665.
- 42Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science 2005; 307: 1915–1920.
- 43Sonnenburg JL, et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 2005; 307: 1955–1959.
- 44Kaoutari AE, Armougom F, Gordon JI, Raoult D, Henrissat B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nat Rev Microbiol 2013; 11: 497–504.
- 45Koropatkin NM, Cameron EA, Martens EC. How glycan metabolism shapes the human gut microbiota. Nat Rev Microbiol 2012; 10: 323–335.
- 46Larsbrink J, et al. A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes. Nature 2014; 506: 498–502.
- 47An G, et al. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med 2007; 204: 1417–1429.
- 48Fu J, et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis. J Clin Invest 2011; 121: 1657–1666.
- 49Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 2008; 27: 104–119.
- 50Donohoe DR, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011; 13: 517–526.
- 51Brestoff JR, Artis D. Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 2013; 14: 676–684.
- 52Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242–249.
- 53De VF, et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014; 156: 84–96.
- 54Tu QV, McGuckin MA, Mendz GL. Campylobacter jejuni response to human mucin MUC2: modulation of colonization and pathogenicity determinants. J Med Micribiol 2008; 57: 795–802.
- 55Bergstrom KSB, et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog 2010; 6: e1000902.
- 56Gustafsson JK, et al. Dynamic changes in mucus thickness and ion secretion during Citrobacter rodentium infection and clearance. PLoS ONE 2013; 8: e84430.
- 57Zarepour M, et al. The mucin Muc2 limits pathogen burdens and epithelial barrier dysfunction during Salmonella enterica serovar Typhimurium colitis. Infect Immun 2013; 81: 3672–3683.
- 58Nikitas G, Deschamps C, Disson O, Niault T, Cossart P, Lecuit M. Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin. J Exp Med 2011; 208: 2263–2277.
- 59Lidell ME, Moncada DM, Chadee K, Hansson GC. Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal part and dissolves the protective colonic mucus gel. Proc Natl Acad Sci USA 2006; 103: 9298–9393.
- 60van der Post S, et al. Site-specific O-glycosylation on the MUC2 mucin inhibits cleavage by the Porphyromonas gingivalis secreted cysteine protease (RgpB). J Biol Chem 2013; 288: 14636–14646.
- 61Buisine MP, et al. Mucin gene expression in human embryonic and fetal intestine. Gut 1998; 43: 519–524.
- 62Birchenough GMH, et al. Altered innate defenses in the neonatal gastrointestinal tract in response to colonization by neuropathogenic Escherichia coli. Infect Immun 2013; 81: 3264–3275.
- 63McElroy SJ, Prince LS, Weitkamp JH, Reese J, Slaughter JC, Polk DB. Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2011; 301: G656–G666.
- 64Karlsson NG, et al. Molecular characterization of the large heavily glycosylated domain glycopeptide from the rat small intestinal Muc2 mucin. Glycoconj J 1996; 13: 823–831.
- 65Hansson GC, Baeckstrom D, Carlstedt I, Klinga-Levan K. Molecular cloning of a cDNA coding for a region of an apoprotein from the insoluble mucin complex of rat small intestine. Biochem Biophys Res Commun 1994; 198: 181–190.
- 66Gum JR, Hicks JW, Toribara NW, Siddiki B, Kim YS. Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. J Biol Chem 1994; 269: 2440–2446.
- 67Tsuru A, et al. Negative feedback by IRE1+¦ optimizes mucin production in goblet cells. Proc Natl Acad Sci USA 1994; 110: 2864–2869.
- 68Martino MB, et al. The ER stress transducer IRE1b is required for airway epithelial mucin production. Mucosal Immunol 2013; 6: 639–654.
- 69Bertolotti A, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1b-deficient mice. J Clin Invest 2001; 107: 585–593.
- 70Kaser A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008; 134: 743–756.
- 71Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol 2010; 28: 573–621.
- 72Higa A, et al. Role of pro-oncogenic protein disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) in the control of endoplasmic reticulum homeostasis. J Biol Chem 2011; 286: 44855–44868.
- 73Gupta A, Dong A, Lowe AW. AGR2 gene function requires a unique endoplasmic reticulum localization motif. J Biol Chem 2012; 287: 4773–4782.
- 74Zhao F, et al. Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2-/- mice. Dev Biol 2010; 338: 270–279.
- 75Bennett EP, Mandel U, Clausen H, Gerken TA, Fritz TA, Tabak LA. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology 2012; 22: 736–756.
- 76Godl K, et al. The N-termini of the MUC2 mucin form trimers that are held together within a trypsin-resistant core fragment. J Biol Chem 2012; 277: 47248–47256.
- 77McDole JR, et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 2012; 483: 345–349.
- 78Patel KK, et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J 2013; 32: 3130–3144.
- 79Razi M, Chan EY, Tooze SA. Early endosomes and endosomal coatomer are required for autophagy. J Cell Biol 2009; 185: 305–321.
- 80Hampe J, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2007; 39: 207–211.
- 81Cadwell K, et al. A key role for autophagy and the autophagy gene Atg16 l1 in mouse and human intestinal Paneth cells. Nature 2007; 456: 259–263.
- 82Ishibashi K, Uemura T, Waguri S, Fukuda M. Atg16L1, an essential factor for canonical autophagy, participates in hormone secretion from PC12 cells independently of autophagic activity. Mol Biol Cell 2012; 23: 3193–3202.
- 83Rescigno M, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2001; 2: 361–367.
- 84Rescigno M, Rotta G, Valzasina B, Ricciardi-Castagnoli P. Dendritic cells shuttle microbes across gut epithelial monolayers. Immunobiology 2001; 204: 572–581.
- 85Ito S. Structure and function of the glycocalyx. Fed Proc 1969; 28: 12–25.
- 86Maury J, Bernadac A, Rigal A, Maroux S. Expression and glycosylation of the filamentous brush border glycocalyx (FBBG) during rabbit enterocyte differentiation along the crypt-villus axis. J Cell Sci 1995; 108: 2705–2713.
- 87Egberts HJA, Koninkx JFJG, van Dijk JE, Mouwen JM. Biological and pathobiological aspects of the glycocalyx of the small intestinal epithelium. A review. Vet Q 1984; 6: 186–199.
- 88Pelaseyed T, Gustafsson JK, Gustafsson IJ, Ermund A, Hansson GC. Carbachol-induced MUC17 endocytosis is concomitant with NHE3 internalization and CFTR membrane recruitment in enterocytes. Am J Physiol Cell Physiol 2013; 305: C457–C467.
- 89Kesimer M, Ehre C, Burns KA, Davis CW, Sheehan JK, Pickles RJ. Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways. Mucosal Immunol 2013; 6: 379–392.
- 90Argueso P, Guzman-Aranguez A, Mantelli F, Cao Z, Ricciuto J, Panjwani N. Association of cell surface mucins with galectin-3 contributes to the ocular surface epithelial barrier. J Biol Chem 2009; 284: 23037–23045.
- 91Linden SK, Sutton P, Karlsson NG, Korolik V, McGuckin MA. Mucins in the mucosal barrier to infection. Mucosal Immunol 2008; 1: 183–197.
- 92Gum JR, et al. Molecular cloning of cDNAs derived from a novel human intestinal mucin gene. Biochem Biophys Res Commun 1990; 171: 407–415.
- 93Gum JR, et al. MUC3 human intestinal mucin. J Biol Chem 1997; 272: 26678–26686.
- 94Williams SJ, McGuckin MA, Gotley DC, Eyre HJ, Sutherland GR, Antalis TM. Two novel mucin genes down-regulated in colorectal cancer identified by differential display. Cancer Res 1999; 59: 4083–4089.
- 95Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR, McGuckin MA. MUC13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J Biol Chem 2001; 276: 18327–18336.
- 96Yin BWT, Lloyd K. Molecular cloning of the CA125 ovarian cancer antigen. J Biol Chem 2001; 276: 27371–27375.
- 97O'Brien TJ, Beard JB, Underwood LJ, Shigemasa K. The CA125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure. Tumour Biol 2002; 23: 154–169.
- 98Gum JR, Crawley SC, Hicks JW, Szymkowski DE, Kim YS. MUC17, a novel membrane-tethered mucin. Biochem Biophys Res Commun 2002; 291: 466–475.
- 99Lang T, Hansson GC, Samuelsson T. Gel-forming mucins appeared early in metazoan evolution. Proc Natl Acad Sci USA 2007; 104: 16209–16214.
- 100Macao B, Johansson DGA, Hansson GC, Härd T. Auto-proteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin. Nat Struct Mol Biol 2006; 13: 71–76.
- 101Lidell ME, Johansson MEV, Hansson GC. An autocatalytic cleavage in the C-terminus of the human MUC2 mucin occurs at the low pH of the late secretory pathway. J Biol Chem 2003; 278: 13944–13951.
- 102Pelaseyed T, Zäch M, Petersson AC, Svensson F, Johansson DG, Hansson GC. Unfolding dynamics of the mucin SEA domain probed by force spectroscopy suggest that it acts as a cell protective device. FEBS J 2013; 280: 1491–1501.
- 103Linden SK, et al. MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy. PLoS Pathog 2009; 5: e1000617.
- 104Hinojosa-Kurtzberg M, Johansson MEV, Madsen CS, Hansson GC, Gendler SJ. Novel MUC1 splice variants contribute to mucin over-expression in CFTR deficient mice. Am J Physiol Gastrointest Liver Physiol 2003; 284: G853–G862.
- 105Sheng YH, et al. MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli. Mucosal Immunol 2013; 6: 557–568.
- 106Sheng YH, et al. The MUC13 cell-surface mucin protects against intestinal inflammation by inhibiting epithelial cell apoptosis. Gut 2011; 60: 1661–1670.
- 107Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol 2008; 70: 431–457.
- 108Malmberg EK, et al. The transmembrane MUC17 mucin C-terminus binds to the scaffold protein PDZK1 that stably localizes it to the enterocyte apical membrane in the small intestine. Biochem J 2008; 410: 283–289.
- 109Donowitz M, et al. NHERF family and NHE3 regulation. J Physiol 2005; 567: 3–11.
- 110Lamprecht G, Seidler UE. The emerging role of PDZ adapter proteins for regulation of intestinal ion transport. Am J Physiol Gastrointest Liver Physiol 2006; 291: G766–G777.
- 111Wang S, Yue H, Derin RB, Guggino WB, Li M. Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity. Cell 2000; 103: 169–179.
- 112Pelaseyed T, Hansson GC. CFTR anion channel modulates expression of human transmembrane mucin MUC3 via the PDZ protein GOPC. J Cell Sci 2011; 124: 3074–3083.
- 113Cheng J, Wang H, Guggino WB. Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. J Biol Chem 2004; 279: 1892–1898.
- 114Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009; 9: 799–809.
- 115Swamy M, Jamora C, Havran W, Hayday A. Epithelial decision makers: in search of the ‘epimmunome’. Nat Immunol 2010; 11: 656–665.
- 116Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol 2014; 14: 9–23.
- 117Song DH, Lee JO. Sensing of microbial molecular patterns by Toll-like receptors. Immunol Rev 2012; 250: 216–229.
- 118Cheroutre H. IELs: enforcing law and order in the court of the intestinal epithelium. Immunol Rev 2005; 206: 114–131.
- 119Witherden DA, Havran WL. Cross-talk between intraepithelial gd T cells and epithelial cells. J Leukoc Biol 2013; 94: 69–76.
- 120Bas A, et al. Butyrophilin-like 1 encodes an enterocyte protein that selectively regulates functional interactions with T lymphocytes. Proc Natl Acad Sci USA 2011; 108: 4376–4381.
- 121Abeler-Dörner L, Swamy M, Williams G, Hayday AC, Bas A. Butyrophilins: an emerging family of immune regulators. Trends Immunol 2012; 33: 34–41.
- 122Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science 2010; 327: 656–661.
- 123Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol 2008; 1: 11–22.
- 124Bain CC, et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol 2013; 6: 498–510.
- 125Jaensson E, et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med 2008; 205: 2139–2149.
- 126Burzyn D, Benoist C, Mathis D. Regulatory T cells in nonlymphoid tissues. Nat Immunol 2013; 14: 1007–1013.
- 127Shan M, et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 2013; 342: 447–453.