The scavenging capacity of DMBT1 is impaired by germline deletions

Abstract

The Scavenger Receptor Cysteine-Rich (SRCR) proteins are an archaic group of proteins characterized by the presence of multiple SRCR domains. They are membrane-bound or secreted proteins, which are generally related to host defense systems in animals. Deleted in Malignant Brain Tumors 1 (DMBT1) is a SRCR protein which is secreted in mucosal fluids and involved in host defense by pathogen binding by its SRCR domains. Genetic polymorphism within DMBT1 leads to DMBT1-alleles giving rise to polypeptides with interindividually different numbers of SRCR domains, ranging from 8 SRCR domains (encoded by 6 kb DMBT1 variant) to 13 SRCR domains (encoded by the 8 kb DMBT1 variant). In the present study, we have investigated whether reduction from 13 to 8 amino-terminal SRCR domains leads to reduction of bacterial binding. The 6 kb variant bound ~20–45% less bacteria compared to the 8 kb variant. These results support the hypothesis that genetic variation in DMBT1 may influence microbial defense.

Salivary Scavenger and Agglutinin (SALSA) Is Expressed in Mucosal Epithelial Cells and Decreased in Bronchial Epithelium of Asthmatic Horses

“…It has been hypothesized that shorter SALSA isoforms have reduced ability to agglutinate bacteria, thereby predisposing individuals to a pro-inflammatory response. As such, individuals with short isoforms were considered more prone to Crohn's disease and had reduced bacterial binding, but association with Crohn's disease was not universal (22, 35, 40). In this study, SRCR domain number appeared unrelated to asthmatic status, however, analysis of 10 individuals is insufficient to draw conclusions regarding disease association of copy number variants (CNV) in a population.…”

The Bigger Picture: Why Oral Mucosa Heals Better Than Skin

“…Mucin 5B (MUC5B) and salivary agglutinin (SAG) are present in the protein films (pellicles) covering the enamel and epithelial surfaces and influence the microbial colonization of these surfaces [46]. In turn, SAG and mucin 7 (MUC7) are among the major bacteriaagglutinating factors in saliva, as shown by several studies reporting the binding of MUC7 and SAG to a variety of (oral) microorganisms (e.g., Streptococcus sanguis, Streptococcus mitis, Streptococcus gordonii, Aggregatibacter actinomycetemcomitans, P. aeruginosa, and Escherichia coli) [47][48][49][50]. Moreover, saliva contains many other antimicrobial peptides and enzymes such as defensins, histatins, cathelicidin (LL-37), lysozyme, lactoferrin, and lactoperoxidase, which synergistically eliminate microorganisms [45,46,51,52].…”

DMBT1 inhibition of Pseudomonas aeruginosa twitching motility involves its N-glycosylation and cannot be conferred by the Scavenger Receptor Cysteine-Rich bacteria-binding peptide domain

“…DMBT1 is expressed in multiple tissues and body fluids and can undergo modifications that affect its function at specific sites 1,9 . Indeed, there are different human DMBT1 alleles within the population and different isoforms in various tissues due to alternative splicing and post-translational modifications 1,4,10–12 . In salivary-derived DMBT1 SAG , ~25% of the molecular mass is due to glycosylation (~10% for N-glycosylation, and ~15% for O-glycosylation) 13,14 .…”