Alternative titles; symbols
HGNC Approved Gene Symbol: BPIFA1
Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38) : 20:33,235,996-33,243,306 (from NCBI)
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 defense. A well-established family of 4 proteins involved in this process includes BPI (109195) and LBP (151990), which are central to the host defense against bacteria, and CETP (118470) and PLTP (172425), which have also been implicated in this response. Bingle and Craven (2002) described a family of 7 candidate host defense proteins in humans, which they designated PLUNC for palate, lung, and nasal epithelium clone.
Weston et al. (1999) used differential display to identify a gene transcript that was expressed in the presumptive nasal epithelium of the mouse embryo. In situ hybridization analysis showed discrete regions of expression associated with the palate, nasal septum, nasal conchae, adult trachea, and bronchi of the lung. They designated the gene Plunc.
Bingle and Bingle (2000) reported the cloning and characterization of the human homolog of Plunc. The cDNA encodes a leucine-rich protein of 256 amino acids that is 72% identical to the murine protein. They demonstrated by RNA blot analysis that expression of PLUNC was restricted to the trachea, upper airway, nasopharyngeal epithelium, and salivary gland.
Bingle and Craven (2002) uncovered the family of PLUNC genes by searching of sequence databases using the PLUNC sequence as a starting point. They noted that 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. Expression data showed that PLUNC proteins are found in overlapping regions of the pulmonary, nasopharyngeal, and oral epithelium, sites where the BPI family members are not expressed. Bingle and Craven (2002) split the 7 PLUNC family members into short (SPLUNC; less than 256 amino acids) and long (LPLUNC; more than 458 amino acids) groups. They noted that within the human PLUNC family, amino acid sequence identity is low, ranging from 16 to 28%. Members of the BPI family are predicted to share very closely similar 3-dimensional structures, whereas 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.
Sung et al. (2002) found that rat Plunc mRNA was expressed in heart, lung, thymus, and salivary gland, as well as in nasal epithelium. Western blot analysis detected a 31-kD protein in rat lung, heart, and spleen and in rat and human mucus. In situ hybridization and immunohistochemical analyses detected expression on the microvilli layer of respiratory epithelium, and expression was upregulated on the ipsilateral side after olfactory bulbectomy.
Bingle and Craven (2002) suggested 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.
Using multiple techniques, Chu et al. (2007) showed that human and mouse bronchial epithelial cells expressed SPLUNC1. Expression of SPLUNC1 decreased Mycoplasma pneumoniae (Mp) levels and inhibited IL8 (146930) production. Conversely, SPLUNC1 RNA interference enhanced Mp growth and IL8 production. IL13 (147683) significantly decreased SPLUNC1 expression and Mp clearance. Chu et al. (2007) concluded that SPLUNC1 is a host-defense protein against Mp. They suggested that in an allergic setting, such as in asthma with increased IL13 expression, SPLUNC1 expression is reduced, which may in part account for the role of Mp and other respiratory infections in asthma pathobiology.
The multisubunit epithelial Na+ channel (ENaC; see 600228) must be proteolytically activated before it can conduct Na+ and absorb excess mucosal liquid in airways. Using mass spectrometric and Western blot analyses, Garcia-Caballero et al. (2009) found that normal human bronchial epithelial cultures secreted SPLUNC1, which could inhibit proteolytic activation of ENaC. SPLUNC1 did not show intrinsic antiprotease activity, but immunoprecipitation analysis revealed that SPLUNC1 directly bound all 3 ENaC subunits. Recombinant SPLUNC1 inhibited ENaC activity in human bronchial epithelial cultures and in Xenopus oocytes. Knockdown of SPLUNC1 by short hairpin RNA resulted in failure of bronchial epithelial cultures to regulate surface liquid height and transepithelial voltage. Garcia-Caballero et al. (2009) concluded that SPLUNC1 binds and blocks ENaC from proteolytic activation. They proposed that SPLUNC1 acts as a reporter molecule whose concentration in airway fluid can adjust ENaC activity and regulate airway hydration.
Bingle and Bingle (2000) determined that the human PLUNC gene contains 9 exons and covers 7.3 kb; the first and last exons are noncoding.
Bingle and Bingle (2000) noted that the EST (Z24371) corresponding to the microsatellite marker D20S195 contained portions of exons 2 and 3 of PLUNC. The clone had been localized to chromosome 20q11.2 by Tomer et al. (1998). Linkage of human PLUNC (BPIFA1) to chromosome 20 was unequivocally confirmed by the existence of partial genomic clones in the chromosome 20 sequencing project database.
Bingle and Craven (2002) mapped 3 mouse Plunc orthologs to chromosome 2, which is syntenic with human chromosome 20q11.
He et al. (2005) screened all exons, relevant exon-intron boundaries, and the approximately 2-kb promoter region of the PLUNC gene (BPIFA1) and identified 8 SNPs. Three haplotype-tagged SNPs were genotyped in a case-control Chinese population composed of 239 unrelated patients with nasopharyngeal carcinoma (NPC; 161550) and 286 healthy controls. Two promoter SNPs, -2128T-C and -1888T-C, showed significant associations with susceptibility to NPC (OR = 2.8, p less than 0.0006, and OR = 3.3, p less than 0.0001, respectively). The distribution of haplotypes constructed based on the -2128T-C and -1888T-C polymorphisms was significantly different between NPC patients and controls: individuals with the C/C haplotype had significantly increased susceptibility to NPC (OR = 1.86, p = 0.00016). He et al. (2005) concluded that genetic variation in BPIFA1 may influence susceptibility to NPC in the Chinese population.
Liu et al. (2013) observed increased susceptibility to Pseudomonas aeruginosa infection and accelerated mortality in mice lacking Splunc1. Splunc1-null mice exhibited significantly elevated inflammatory cytokine and chemokine production. They also showed decreased expression of several secretory proteins, including mucins (e.g., MUC5AC; 158373) and club cell secretory protein (SCGB1A1; 192020), and antimicrobial proteins, including LL37 (600474), lactotransferrin (LTF; 150210), and lysozyme (LYZ; 153450), in lung. P. aeruginosa had an enhanced ability to form biofilms in the absence of Splunc1, and biofilm formation could be inhibited by administration of recombinant Splunc1. Liu et al. (2013) proposed that loss of Splunc1 in mouse airways affected mucociliary clearance, leading to decreased innate immunity during P. aeruginosa infection.
Bingle, C. D., Bingle, L. Characterisation of the human plunc gene, a gene product with an upper airways and nasopharyngeal restricted expression pattern. Biochim. Biophys. Acta 1493: 363-367, 2000. [PubMed: 11018263] [Full Text: https://doi.org/10.1016/s0167-4781(00)00196-2]
Bingle, C. D., Craven, C. J. PLUNC: A novel family of candidate host defence proteins expressed in the upper airways and nasopharynx. Hum. Molec. Genet. 11: 937-943, 2002. [PubMed: 11971875] [Full Text: https://doi.org/10.1093/hmg/11.8.937]
Chu, H. W., Thaikoottathil, J., Rino, J. G., Zhang, G., Wu, Q., Moss, T., Refaeli, Y., Bowler, R., Wenzel, S. E., Chen, Z., Zdunek, J., Breed, R., Young, R., Allaire, E., Martin, R. J. Function and regulation of SPLUNC1 protein in mycoplasma infection and allergic inflammation. J. Immun. 179: 3995-4002, 2007. [PubMed: 17785838] [Full Text: https://doi.org/10.4049/jimmunol.179.6.3995]
Garcia-Caballero, A., Rasmussen, J. E., Gaillard, E., Watson, M. J., Olsen, J. C., Donaldson, S. H., Stutts, M. J., Tarran, R. SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage. Proc. Nat. Acad. Sci. 106: 11412-11417, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 106: 15091 only, 2009. [PubMed: 19541605] [Full Text: https://doi.org/10.1073/pnas.0903609106]
He, Y., Zhou, G., Zhai, Y., Dong, X., Lv, L., He, F., Yao, K. Association of PLUNC gene polymorphisms with susceptibility to nasopharyngeal carcinoma in a Chinese population. (Letter) J. Med. Genet. 42: 172-176, 2005. [PubMed: 15689457] [Full Text: https://doi.org/10.1136/jmg.2004.022616]
Liu, Y., Di, M. E., Chu, H. W., Liu, X., Wang, L., Wenzel, S., Di, Y. P. Increased susceptibility to pulmonary Pseudomonas infection in Splunc1 knockout mice. J. Immun. 191: 4259-4268, 2013. [PubMed: 24048904] [Full Text: https://doi.org/10.4049/jimmunol.1202340]
Sung, Y. K., Moon, C., Yoo, J.-Y., Moon, C., Pearse, D., Pevsner, J., Ronnett, G. V. Plunc, a member of the secretory gland protein family, is up-regulated in nasal respiratory epithelium after olfactory bulbectomy. J. Biol. Chem. 277: 12762-12769, 2002. [PubMed: 11821380] [Full Text: https://doi.org/10.1074/jbc.M106208200]
Tomer, Y., Barbesino, G., Greenberg, D. A., Concepcion, E., Davies, T. F., International Consortium for the Genetics of Autoimmune Thyroid Disease. A new Graves disease-susceptibility locus maps to chromosome 20q11.2. Am. J. Hum. Genet. 63: 1749-1756, 1998. [PubMed: 9837828] [Full Text: https://doi.org/10.1086/302146]
Weston, W. M., LeClair, E. E., Trzyna, W., McHugh, K. M., Nugent, P., Lafferty, C. M., Ma, L., Tuan, R. S., Greene, R. M. Differential display identification of plunc, a novel gene expressed in embryonic palate, nasal epithelium, and adult lung. J. Biol. Chem. 274: 13698-13703, 1999. Note: Erratum: J. Biol. Chem. 275: 8262 only, 2000. [PubMed: 10224143] [Full Text: https://doi.org/10.1074/jbc.274.19.13698]