Defensins, lectins, mucins, and secretory immunoglobulin A: microbe-binding biomolecules that contribute to mucosal immunity in the human gut

Abstract

In the intestine, the mucosal immune system plays essential roles in maintaining homeostasis between the host and microorganisms, and protecting the host from pathogenic invaders. Epithelial cells produce and release a variety of biomolecules into the mucosa and lumen that contribute to immunity. In this review, we focus on a subset of these remarkable host-defense factors - enteric α-defensins, select lectins, mucins, and secretory immunoglobulin A - that have the capacity to bind microbes and thereby contribute to barrier function in the human gut. We provide an overview of the intestinal epithelium, describe specialized secretory cells named Paneth cells, and summarize our current understanding of the biophysical and functional properties of these select microbe-binding biomolecules. We intend for this compilation to complement prior reviews on intestinal host-defense factors, highlight recent advances in the field, and motivate investigations that further illuminate molecular mechanisms as well as the interplay between these molecules and microbes.

Keywords: Mucosal immunity; Paneth cells; defensins; host defense; lectins; mucins; sIgA.

Figure 1

The physical and chemical barriers in a crypt of small intestine. Intestinal epithelial cells form physical and chemical barriers that segregate the luminal microbial community and the mucosal immune system. HDP = host-defense peptide; sIgA = secretory immunoglobulin A. A color version of the figure is available online.

Figure 2

Primary sequences and X-ray crystal structures of select defensins. HD6 (PDB 1ZMQ (Szyk et al., 2006)), HBD1 (PDB 1IJV (Hoover et al., 2001)), and RTD1 (PDB 1HVZ (Trabi et al., 2001)) are representatives of α-, β-, and θ-defensin, respectively. The disulfide linkages are shown in yellow. A color version of the figure is available online.

Figure 3

Defensins are expressed as prepropeptides and exhibit several conserved features. (A) A cartoon represents a prepropeptide. The black arrow indicates the position where a protease cleaves and releases a mature defensin. (B) Amino acid sequences of mature α-defensins in which conserved features are highlighted: cysteine residues and regiospecific disulfide linkages are shown in red, a salt bridge between Arg and Glu residues is shown in blue, a Gly residue in a GXC motif is shown green. A color version of the figure is available online.

Figure 4

Overview of HD5. (A) The amino acid sequence of HD5 and a cartoon showing its secondary structure. The solid red lines represent the disulfide linkages. (B) Crystal structures of HD5 monomer (left) and dimer (right) (PDB 1ZMP (Szyk et al., 2006)). The hydrophobic residues of HD5 are distributed at the tetrameric interface, whereas the Arg residues are distributed on the opposite face of the dimer, which is exposed to the surface after tetramerization. The hydrophobic residues are shown in orange and the Arg residues are shown in pink. A color version of the figure is available online.

Figure 5

Overview of HD6. (A) The amino acid sequence of HD6 and a cartoon showing its secondary structure. The solid red lines represent the disulfide linkages. (B) Crystal structure of HD6 monomer (PDB 1ZMQ (Szyk et al., 2006)) with disulfide bonds shown in yellow. A color version of the figure is available online.

Figure 6

Self-assembly of HD6. (A) Transmission electron micrograph of 20 µM HD6 in 10 mM sodium phosphate, pH 7.4. (B) Crystal structure of HD6 monomers (PDB 1ZMQ (Szyk et al., 2006)) showing the hydrophobic pocket that drives the self-assembly of HD6. Individual HD6 monomers are labeled as a–d. A color version of the figure is available online.

Figure 7

Structures of mucins. The structure of mucin 1 (MUC1) represents the typical structure of membrane-bound mucins in the GI tract. The extracellular TRR is heavily O-glycosylated, and the protein is N-glycosylated near the SEA domain. The cytoplasmic domain of MUC1 is involved in intracellular transduction. Mucin 2 (MUC2) is a major component of the secreted mucus barrier in the intestine. The TRRs are heavily O-glycosylated and the N- and C-terminal D domains are involved in homo-oligomerization. A color version of the figure is available online.

Figure 8

A cartoon represents the overview structure of sIgA. SIgA are dimeric with two IgA molecules held together by a joining chain (J-chain). Each IgA molecule consists of two heavy chains and two light chains. The secretory component protects the antibody from being degraded by the enzymes of the digestive system. A color version of the figure is available online.