BPIFA1 explained

BPI fold containing family A, member 1 (BPIFA1), also known as Palate, lung, and nasal epithelium clone (PLUNC),^[1] is a protein that in humans is encoded by the BPIFA1 gene.^{[2] [3]} It was also formerly known as "Secretory protein in upper respiratory tracts" (SPURT). The BPIFA1 gene sequence predicts 4 transcripts (splice variants); 3 mRNA variants have been well characterized. The resulting BPIFA1 is a secreted protein, expressed at very high levels in mucosa of the airways (olfactory and respiratory and epithelium) and salivary glands; at high levels in oropharyneal epithelium, including tongue and tonsils; and at moderate levels many other tissue types and glands including pituitary, testis, lung, bladder, blood, prostate, pancreas, levels in the digestive tract (tongue, stomach, intestinal epithelium) and pancreas.^[4] The protein can be detected on the apical side of epithelial cells and in airway surface liquid, nasal mucus, and sputum.^[5]

Superfamily

BPIFA1 is a member of a BPI fold protein superfamily defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape.^[6] This superfamily is also known as the BPI/LBP/PLUNC family or the BPI/LPB/CETP family.^[7] The BPI fold creates apolar binding pockets that can interact with hydrophobic and amphipathic molecules, such as the acyl carbon chains of lipopolysaccharide found on Gram-negative bacteria, but members of this family may have many other functions.

Genes for the BPI/LBP/PLUNC superfamily are found in all vertebrate species, including distant homologs in non-vertebrate species such as insects, mollusks, and roundworms.^{[8] [9]} Within that broad grouping is the BPIF gene family whose members encode the BPI fold structural motif and are found clustered on a single chromosome, e.g., Chromosome 20 in humans, Chromosome 2 in mouse, Chromosome 3 in rat, Chromosome 17 in pig, Chromosome 13 in cow. The BPIF gene family is split into two groupings, BPIFA and BPIFB. In humans, BIPFA consists of 3 protein encoding genes BPIFA1, BPIFA2, BPIFA3, and 1 pseudogene BPIFA4P; while BPIFB consists of 5 protein encoding genes BPIFB1, BPIFB2, BPIFB3, BPIFB4, BPIFB6 and 2 pseudogenes BPIFB5P, BPIFB9P. What appears as pseudogenes in humans may appear as fully functional genes in other species.

In humans, the BPIFA1 gene was first identified as an ortholog of the mouse Plunc gene^[3] which had earlier been identified from a differential display screen of the embryonic mouse palate.^[10] Subsequently, using microarray analysis techniques of human epithelial tissues, the SPURT gene and, separately, the SPLUNC1 gene were identified.^{[11] [12]} These were all recognized to be, in fact, the same gene within the BPI/LBP/PLUNC family.

Function

BPIFA1 has multiple functions but perhaps its most prominent ones are related to BPIFA1's localization in nasal, olfactory, oral, and respiratory epithelium and the mucous/fluids that coat them. BPIFA1/SPLUNC1 binds with high affinity and specificity to dipalmitoylphosphatidylcholine, one of the major and most important surfactant phospholipids in the airway and lungs.^[13] By lowering the surface tension in mucosal fluids, BPIFA1/SPLUNC1 inhibits bacteria like Klebsiella from proliferating as a biofilm on epithelium.^[14] The protein physically interacts with pathogens, causing "bacterial cell coating" that inhibits the epithelial sodium channel of bacteria, makes bacteria like Pseudomonas more permeable, and attracts macrophages and neutrophils for a bactericidal effect. ^{[15] [16]} As such, BPIFA1 plays a role in innate immune defense in the airways.

BPIFA1/PLUNC's ability to regulate ENaC is pH-sensitive and fails in acidic cystic fibrosis airways.^[17] Thus, defective BPIFA1/PLUNC1 gene function is thought to contribute to the development of lung pathology in cystic fibrosis patients.

It may also serve as a potential molecular marker for detection of micrometastasis in non-small-cell lung cancer.^[18]

Further reading

• Garcia-Caballero A, Rasmussen JE, Gaillard E, Watson MJ, Olsen JC, Donaldson SH, Stutts MJ, Tarran R . SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage . Proceedings of the National Academy of Sciences of the United States of America . 106 . 27 . 11412–7 . Jul 2009 . 19541605 . 2708735 . 10.1073/pnas.0903609106 . 2009PNAS..10611412G . free .
• Zhang BC, Zhu SG, Xiang JJ, Zhou M, Nie XM, Xiao BY, Li XL, Li GY . [Analysis of splicing variants in NASG 3'UTR, down-regulated in nasopharyngeal carcinoma, and its expression in multiple cancer tissues] . AI Zheng = Aizheng = Chinese Journal of Cancer . 22 . 5 . 477–80 . May 2003 . 12753706 .
• Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, Caprau D, Zimmerman CR, Steffen KM, Johnson KJ, Marazita ML, Murray JC . Determination of genetic predisposition to patent ductus arteriosus in preterm infants . Pediatrics . 123 . 4 . 1116–23 . Apr 2009 . 19336370 . 2734952 . 10.1542/peds.2008-0313 .
• Bryborn M, Halldén C, Säll T, Cardell LO . CLC- a novel susceptibility gene for allergic rhinitis? . Allergy . 65 . 2 . 220–8 . Feb 2010 . 19650845 . 10.1111/j.1398-9995.2009.02141.x . 29636426 .
• Cheng M, Chen Y, Yu X, Tian Z, Wei H . Diagnostic utility of LunX mRNA in peripheral blood and pleural fluid in patients with primary non-small cell lung cancer . BMC Cancer . 8 . 156 . 2008 . 18513434 . 2424066 . 10.1186/1471-2407-8-156 . free .
• Zhou HD, Li GY, Yang YX, Li XL, Sheng SR, Zhang WL, Zhao J . Intracellular co-localization of SPLUNC1 protein with nanobacteria in nasopharyngeal carcinoma epithelia HNE1 cells depended on the bactericidal permeability increasing protein domain . Molecular Immunology . 43 . 11 . 1864–71 . Apr 2006 . 16364440 . 10.1016/j.molimm.2005.10.021 .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Zhou HD, Fan SQ, Zhao J, Huang DH, Zhou M, Liu HY, Zeng ZY, Yang YX, Huang H, Li XL, Shen SR, Li GY . Tissue distribution of the secretory protein, SPLUNC1, in the human fetus . Histochemistry and Cell Biology . 125 . 3 . 315–24 . Mar 2006 . 16195890 . 10.1007/s00418-005-0070-4 . 20600762 .
• Sentani K, Oue N, Sakamoto N, Arihiro K, Aoyagi K, Sasaki H, Yasui W . Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach . Modern Pathology . 21 . 4 . 464–75 . Apr 2008 . 18204429 . 10.1038/modpathol.3801050 . free .
• Campos MA, Abreu AR, Nlend MC, Cobas MA, Conner GE, Whitney PL . Purification and characterization of PLUNC from human tracheobronchial secretions . American Journal of Respiratory Cell and Molecular Biology . 30 . 2 . 184–92 . Feb 2004 . 12920053 . 10.1165/rcmb.2003-0142OC .
• He Y, Ding YQ, Huang ZX, Yao KT . [Association of the coding region single nucleotide polymorphisms in PLUNC gene with nasopharyngeal carcinoma] . Zhonghua Yi Xue Za Zhi . 87 . 22 . 1553–5 . Jun 2007 . 17785110 .
• Wang WB, Cui YG, Yao SY . [Message RNA expression of LUNX, CK19 and CEA genes in NSCLC with micrometastasis in lymph nodes] . Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology] . 30 . 2 . 121–4 . Feb 2008 . 18646695 .
• Bartlett JA, Hicks BJ, Schlomann JM, Ramachandran S, Nauseef WM, McCray PB . PLUNC is a secreted product of neutrophil granules . Journal of Leukocyte Biology . 83 . 5 . 1201–6 . May 2008 . 18245229 . 10.1189/jlb.0507302 . 19196781 . free .
• Zhou HD, Li XL, Li GY, Zhou M, Liu HY, Yang YX, Deng T, Ma J, Sheng SR . Effect of SPLUNC1 protein on the Pseudomonas aeruginosa and Epstein-Barr virus . Molecular and Cellular Biochemistry . 309 . 1–2 . 191–7 . Feb 2008 . 18049866 . 10.1007/s11010-007-9659-3 . 23343796 .
• Bingle L, Barnes FA, Cross SS, Rassl D, Wallace WA, Campos MA, Bingle CD . Differential epithelial expression of the putative innate immune molecule SPLUNC1 in cystic fibrosis . Respiratory Research . 8 . 79 . 2007 . 1 . 17988392 . 2203987 . 10.1186/1465-9921-8-79 . free .

Notes and References

1. Ghafouri. B.. PLUNC (palate, lung and nasal epithelial clone) proteins in human nasal lavage fluid. Biochem Soc Trans. 12887311. 31. 4. 810–4. 10.1042/bst0310810. 2003.
2. Web site: BPIFA1 BPI fold containing family A member 1 [Homo sapiens (human)] - Gene - NCBI ]. www.ncbi.nlm.nih.gov.
3. Bingle CD, Bingle L . Characterisation of the human plunc gene, a gene product with an upper airways and nasopharyngeal restricted expression pattern . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1493 . 3 . 363–7 . Oct 2000 . 11018263 . 10.1016/S0167-4781(00)00196-2 .
4. Web site: Gene : BPIFA1 - ENSG00000198183 . bgee.org . The Bgee suite: integrated curated expression atlas and comparative transcriptomics in animals.
5. Web site: Q9NP55 - BPIA1_HUMAN . www.uniprot.org.
6. Beamer LJ, Carroll SF, Eisenberg D . The BPI/LBP family of proteins: a structural analysis of conserved regions . Protein Science . 7 . 4 . 906–914 . April 1998 . 9568897 . 2143972 . 10.1002/pro.5560070408 .
7. Web site: CDD Conserved Protein Domain Family: BPI . www.ncbi.nlm.nih.gov.
8. Beamer LJ, Fischer D, Eisenberg D . Detecting distant relatives of mammalian LPS-binding and lipid transport proteins . Protein Science . 7 . 7 . 1643–1646 . July 1998 . 9684900 . 2144061 . 10.1002/pro.5560070721 .
9. Bingle CD, Seal RL, Craven CJ . Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily . Biochemical Society Transactions . 39 . 4 . 977–983 . August 2011 . 21787333 . 3196848 . 10.1042/BST0390977 .
10. Weston WM, LeClair EE, Trzyna W, McHugh LM, Nugent P, Lafferty CM, Ma LL, Tuan RS, Greene RM . Differential Display Identification of plunc, a Novel Gene Expressed in Embryonic Palate, Nasal Epithelium, and Adult Lung . Journal of Biological Chemistry . May 1999 . 274 . 19 . 13698–13703 . 10.1074/jbc.274.19.13698 . 10224143 . free .
11. Di YP, Harper R, Zhao Y, Pahlavan N, Finkbeiner W, Wu R . Molecular Cloning and Characterization of spurt, a Human Novel Gene That Is Retinoic Acid-inducible and Encodes a Secretory Protein Specific in Upper Respiratory Tracts . Journal of Biological Chemistry . January 2003 . 278 . 2 . 1165–1173 . 10.1074/jbc.M210523200 . 12409287 . free .
12. Zhang B, Nie X, Xiao B, Xiang J, Shen S, Gong J, et al. . Identification of tissue-specific genes in nasopharyngeal epithelial tissue and differentially expressed genes in nasopharyngeal carcinoma by suppression subtractive hybridization and cDNA microarray . Genes, Chromosomes and Cancer . September 2003 . 38 . 1 . 80–90 . 10.1002/gcc.10247 . 12874788. 24805514 .
13. Ning F, Wang C, Berry KZ, Kandasamy P, Liu H, Murphy RC, et al. . Structural characterization of the pulmonary innate immune protein SPLUNC1 and identification of lipid ligands . The FASEB Journal . December 2014 . 28 . 12 . 5349–5360 . 10.1096/fj.14-259291 . free . 25223608 . 4232288.
14. Liu Y, Bartlett JA, Di ME, BombergerJM, Chan YR, GakharL, et al. . SPLUNC1/BPIFA1 Contributes to Pulmonary Host Defense against Klebsiella pneumoniae Respiratory Infection . The American Journal of Pathology . May 2013 . 182 . 5 . 1519–1531 . 10.1016/j.ajpath.2013.01.050 . 23499554 . 3644735.
15. Garcia-Caballero A, Rasmussen JE, Gaillard E, Watson MJ, Olsen JC, Donaldson SH, Stutts MJ, Tarran R . SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage . Proceedings of the National Academy of Sciences of the United States of America . 106 . 27 . 11412–7 . Jul 2009 . 19541605 . 2708735 . 10.1073/pnas.0903609106 . 2009PNAS..10611412G . free .
16. Sayeed S, Nistico L, St Croix C, Di YP, et al. . Multifunctional Role of Human SPLUNC1 in Pseudomonas aeruginosa Infection . Infection and Immunity . January 2013 . 81 . 1 . 285–291 . 10.1128/IAI.00500-12 . 23132494 . 3536124.
17. Garland AL, Walton WG, Coakley RD, Tan CD, Gilmore RC, Hobbs CA, Tripathy A, Clunes LA, Bencharit S, Stutts MJ, Betts L, Redinbo MR, Tarran R . Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways . Proceedings of the National Academy of Sciences of the United States of America . 110 . 40 . 15973–8 . Oct 2013 . 24043776 . 3791714 . 10.1073/pnas.1311999110 . 2013PNAS..11015973G . free .
18. Web site: Entrez Gene: PLUNC .