PLUNC: A novel family of candidate host defence proteins expressed in the upper airways and nasopharynx

Abstract

The upper respiratory tract, including the nasal and oral cavities, is the major route of entry of pathogens into the body, and early recognition of bacterial products in this region is critical for host defence. A well-established family of four proteins involved in this process are bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP), which are central to the host defence against bacteria, and cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), which have also been implicated in this response. In this paper, we demonstrate the existence of a related family of seven human proteins, which we designate PLUNC proteins. The PLUNC proteins are encoded by adjacent genes found within a 300 kb region of chromosome 20, suggesting that they may be under transcriptional control of shared genomic elements, and expression data shows that these proteins are found in overlapping regions of the pulmonary, nasopharyngeal and oral epithelium, sites where the previously described BPI family members are not expressed. Whereas the BPI family are predicted to share very closely similar three-dimensional structures, the PLUNC family is predicted to have much greater variability in the N-terminal domain, corresponding to the active domain of BPI, thus creating the notion of a BPI/PLUNC structural superfamily. We suggest that members of the PLUNC family may function in the innate immune response in regions of the mouth, nose and lungs, which are sites of significant bacterial exposure.

SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage

“…Due to the structural similarity between SPLUNC1 and antibacterial proteins such as lipopolysaccharide binding protein (LPB), it has been suggested that SPLUNC1 has an important role in airways innate host defense (14). However, this hypothesis is controversial, and some investigators have found that SPLUNC1 appears to have little antimicrobial activity against Escherichia coli, Listeria monocytogenes, or Pseudomonas aeruginosa (17), and does not appear to bind lipopolysaccharide (15).…”

“…The original PLUNC gene, which is now called SPLUNC1, comprises up to 10% of total protein in the airway surface liquid, and can readily be detected in both nasal lavage and tracheal secretions (14)(15)(16). SPLUNC1 is expressed in both submucosal glands, the superficial epithelia and in neutrophils, and in theory, is present in the correct regions of the lung to be a volume sensing molecule, because it can be secreted onto the mucosal surface of the superficial epithelial where ENaC is expressed (17,18).…”

Characterisation and expression of SPLUNC2, the human orthologue of rodent parotid secretory protein

“…A sample of whole saliva was subjected to deglycosylation using N-Glycanase PNGase F and subjected to western blotting with antibody SPLUNC2B. The multiple bands present on the mock digested sample (lane 8) were reduced to a single band of lower molecular mass following PNGase treatment (lane 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 (Bingle & Craven 2002;. The founding member of this extended family, Palate Lung Nasal Clone (PLUNC), was first described in the nasal epithelium of the mouse embryo and the trachea and bronchi of adult mouse lung (Weston et al 1999).…”

“…The founding member of this extended family, Palate Lung Nasal Clone (PLUNC), was first described in the nasal epithelium of the mouse embryo and the trachea and bronchi of adult mouse lung (Weston et al 1999). Our studies identified a family of human PLUNC proteins located on chromosome 20 (Bingle & Craven 2002) in close proximity to genes encoding the related proteins, lipopolysaccharide binding protein (LBP) and Bactericidal/permeability-increasing protein (BPI), key members of the innate immune response to Gram-negative bacteria. We have previously shown that the PLUNC family can be subdivided into short (SPLUNC) and long (LPLUNC) proteins containing domains predicted to be structurally similar to one or both domains of BPI ( Our comparative studies have revealed that PLUNC proteins are rapidly evolving and exhibit a high level of sequence diversity between orthologues as well as exhibiting lineage specific expansion in the number of paralogues (Bingle & Craven 2002;Wheeler et al 2007).…”

Proteomic analysis of pediatric sinonasal secretions shows increased MUC5B mucin in CRS

“…BPIFA1, which has the highest fold change in CRS sinonasal secretions, is a member of the BPI or PLUNC family of proteins (20) found in secretions from the upper airways, nose, and mouth. While the functions of BPI proteins have not yet been fully elucidated, they appear to have multifunctional roles in airway immune defense.…”