MUC1 mucin: a peacemaker in the lung

Abstract

MUC1 is a membrane-tethered mucin expressed on the surface of epithelial cells lining mucosal surfaces. Recent studies have begun to elucidate the physiologic function of MUC1 in the airways, pointing to an antiinflammatory role that is initiated late in the course of bacterial infection and is mediated through inhibition of TLR signaling. These new findings have great potential for clinical applications in controlling excessive and prolonged lung inflammation. This review briefly summarizes the protein structural features of MUC1 relevant to its function, the discovery of its antiinflammatory properties, and potential directions for future avenues of study.

Figure 1.

Structure of MUC1. (A) The extracellular region contains sites of O- and N-linked glycosylation. Serines and threonines are the sites of O-glycosylation, while asparagines in specific sequences (N-X-S/T) are potential sites of N-glycosylation. The 20–amino acid variable number of tandem repeats (VNTR) is also referred to as the PTS domain due to the preponderance of proline, threonine, and serine residues (colored ovals). Although only 6 VNTRs are shown, their actual number can vary from 25 to 125 in various tissues and/or individuals (3). Proteolysis at the indicated Gly-Ser site creates a heterodimer protein structure. (B) Tyrosine residues (purple) in the MUC1 CT are phosphorylated by the indicated kinases (arrows) and serve as binding sites (boxes) for kinases and adapter proteins. Additional binding sites for GSK3β and β-catenin are indicated. The question mark indicates the action of an unknown kinase.

Figure 2.

Proposed model for the roles of MUC1, TLRs, TNF-α, IL-8, and NF-κB as major players in the response of airway epithelia to bacteria. (Step 1) During the early stage of infection by Pseudomonas aeruginosa (PA), bacterial PAMPs (e.g., flagellin) activate TLRs and NF-κB on epithelial cells and macrophages (M) (2). Activation of NF-κB leads to increased expression of TNF-α and of IL-8, which are subsequently secreted (3). IL-8 recruits neutrophils (N) across the epithelial barrier that release NE into the lumen of the airways (4). NE and TNF-α up-regulate MUC1 gene expression, resulting in increased expression of MUC1 mucin at the apical surface of lung epithelial cells (5). During the late stage of infection, tyrosine phosphorylation of MUC1 CT domain leads to inhibition of TLR signaling and down-regulation of inflammation.