The Role of the Cell Surface Mucin MUC1 as a Barrier to Infection and Regulator of Inflammation

Abstract

The family of cell surface (cs-) mucins are constitutively expressed at the cell surface by nearly all epithelial cells, beneath the gel-mucin layer. All cs-mucin family members have structural features that enable them to act as a releasable decoy barrier to mucosal pathogens, by providing ligands for pathogen binding and the ability to shed the bound extracellular domain. Due to the towering structure of cs-mucins at the surface, binding of mucosal pathogens can also sterically block binding to underlying cellular receptors. The cytoplasmic tail domain of cs-mucins are capable of initiating signal transduction cascades and due to their conservation across species, may play an important biological role in cellular signaling. MUC1 is one of the most extensively studied of the cs-mucin family. With respect to its physiological function in the mucosal environment, MUC1 has been demonstrated to play a dynamic role in protection of the host from infection by a wide variety of pathogens and to regulate inflammatory responses to infection. This review briefly summarizes the current knowledge and new findings regarding the structural features relating to the function of MUC1, its role as a protective barrier against pathogen invasion and mechanisms by which this cs-mucin regulates inflammation.

Keywords: Campylobacter jejuni; Helicobacter pylori; MUC1; NLRP3-inflammasome; Pseudomonas aeruginosa; Streptococcus pneumoniae; influenza A virus; toll-like receptor.

Figure 1

(A) Schematic representation of MUC1. MUC1 consists of a large, extracellular, O-glycosylated polypeptide backbone that extends 200–500 nm above the apical surface and consists of the variable number tandem repeat region (VNTR). The VNTR which is composed of between 25 and 125 repeats of a conserved 20 amino acid sequence. This extracellular domain is heavily 0-glycosylated toward the N-terminal, while closer to the cell membrane, MUC1 displays N-glycans. Next to the VNTR lies the sea-urchin sperm protein, enterokinase and agrin (SEA) domain, which is non-covalently linked to the transmembrane (Tm) region and can undergo autoproteolysis in response to a range of stimuli. The Tm region, which is 28 amino acids in length, tethers MUC1 to the cell membrane. Immediately underlying the Tm region is a 72 amino acid long cytoplasmic tail (-CT), which lies inside the cell. The MUC1-CT is known to interact with multiple signaling cascades. (B) Amino acid sequence of the MUC1-CT and known binding partners. The MUC1-CT contains 7 tyrosine residues (shown in red), along with serine and threonine residues, which serve as docking sites for kinases and other adaptor proteins. Blue bars mark the known binding sites of specific cellular signaling proteins including: β-catenin (Yamamoto et al., 1997); ZAP-70, zeta chain-associated protein kinase-70 (Li et al., 2004); P13K, phosphoinositide 3-kinase (Kato et al., 2007); Shc, Src homology 2 domain containing protein (Li et al., 2001a); PLC-γ, phospholipase C-γ (Wang et al., 2003); GSK3β, glycogen synthase kinase 3β (Li et al., 1998); PKCδ, protein kinase C-δ (Ren et al., 2002); Lck, lymphocyte-specific protein tyrosine kinase (Li et al., 2004); EGFR, epidermal growth factor receptor (Li et al., 2001b); Grb2, growth factor receptor-bound protein 2 (Pandey et al., 1995). The C-terminal end of the CT contains the motif CQC (purple) which has been demonstrated to be essential for localization of MUC1 at the cell membrane (Leng et al., 2007).

Figure 2

Modes of MUC1 control of cellular inflammatory signaling pathways. (A) Infection causes TLR activation, causing production of inflammatory mediators, such as TNF. In turn, MUC1 is upregulated and suppresses TLR signaling, attenuating inflammation. Direct binding of pathogen to MUC1-ED induces phosphorylation of the MUC1 cytoplasmic tail, increasing MUC1-CT association with TLRs at the cell surface, or within the endosome, competitively inhibiting recruitment of MyD88 and/or TRIF to the TLR and blocks downstream signaling. (B) Upon detection of PAMPs by PRRs at the cellular membrane and within the endosome, the TLR becomes activated and induces the NF-kB transcription pathway, resulting in upregulation of pro-IL-1β, pro-IL-18 and pro-caspase-1, ASC and NLRP3. A second stimulus then causes NLRP3 to nucleate ASC, inducing the characteristic speck-like structure and causes caspase-1 activation. Active caspase-1 cleaves the pro-IL-1β and pro-IL-18, creating the active cytokines IL-1β and IL-18, which are then secreted from the cell. (C) Activation of the MUC1-CT after interaction with pathogen causes recruitment to the TLR, and/or subsequent signaling that limits TLR activation of the signaling cascade and blocks upregulation of inflammasome components. Whether MUC1-CT interacts with NLRP3 directly remains to be determined.