Surfactant protein A2 explained

Surfactant protein A2 (SP-A2), also known as Pulmonary surfactant-associated protein A2 (PSP-A2) is a protein that in humans is encoded by the SFTPA2 gene.[1] [2]

Summary

The protein encoded by this gene (SP-A2) is primarily synthesized in lung alveolar type II cells, as part of a complex of lipids and proteins known as pulmonary surfactant. The function of this complex is to reduce surface tension in the alveolus and prevent collapse during expiration. The protein component of surfactant helps in the modulation of the innate immune response, and inflammatory processes.[3]

SP-A2 is a member of a subfamily of C-type lectins called collectins. Together with (surfactant protein A1) SP-A1, they are the most abundant proteins of pulmonary surfactant. SP-A2 binds to the carbohydrates found in the surface of several microorganisms and helps in the defense against respiratory pathogens.[4] [5] [6]

Surfactant homeostasis is critical for breathing (and thus survival) in the prematurely born infant, but also for maintaining lung health, and normal lung function throughout life. Quantitative and/or qualitative alterations in surfactant composition and/or function are associated with respiratory diseases.[7] [8] [9] [10]

SFTPA2 expression

The lung is the main site of SFTPA2 synthesis, but SFTPA2 mRNA expression has also been detected in the trachea, prostate, pancreas, thymus, colon, eye, salivary gland and other tissues. While the majority of these tissues express both SFTPA2 and SFTPA1 transcripts, only SFTPA2 expression was found in the trachea and prostate.[11] Using specific monoclonal antibodies for Surfactant protein A, the protein can be detected in lung alveolar type II pneumocytes, Club cells, and alveolar macrophages, but no extrapulmonary SP-A immunoreactivity was observed.

Gene

SFTPA2 is located in the long arm of chromosome 10, close to SFTPA1. The SFTPA2 gene is 4556 base pairs in length, and 94% similar to SFTPA1. The structure of SFTPA2 consists of four coding exons (I-IV), and several 5'UTR untranslated exons (A, B, B’, C, C’, D, D’).[12] [13] The expression of SFTPA2 is regulated by cellular factors including proteins, small RNAs (microRNAs), glucocorticoids, etc. Its expression is also regulated by epigenetic and environmental factors.[14]

Differences in the SFTPA2 gene sequence at the coding region determine SP-A genetic variants or haplotypes among individuals.[13] More than 30 variants have been identified and characterized for SFTPA2 (and SFTPA1) in the population. SFTPA2 variants result from nucleotide changes in the codons of amino acids 9, 91, 140, and 223. Three of these do not modify the SP-A2 protein sequence (amino acids 9, 91, and 223), whereas the remaining one results in an amino acid substitution (amino acid 140). Six SP-A2 variants (1A, 1A0, 1A1, 1A2, 1A3, 1A5) are in higher frequency in the general population. The most frequently found variant is 1A0.[15] [16]

Structure

SP-A2 is a protein of 248 amino acids usually found in large oligomeric structures. The mature SP-A2 monomer is a 35kDa protein that differs from SP-A1 in four amino acids at the coding region. The structure of SP-A2 monomers consists of four domains: an N-terminal, a collagen-like domain, a neck region, and a carbohydrate recognition domain. The C-terminal carbohydrate recognition domain (CRD) allows binding to various types of microorganisms and molecules.[15] [16] The amino acid differences that distinguish between SFTPA2 and SFTPA1 genes and between their corresponding variants are located at the collagen-like domain. The amino acid differences that distinguish among SFTPA2 variants are located both at the carbohydrate recognition and the collagen-like domains.[15] [17]

SP-A2 monomers group with other SP-A2 or SP-A1 monomers in trimeric structural subunits of 105kDa. Six of these structures group in 630 kDa structures that resemble flower bouquets. These oligomers contain a total of eighteen SP-A2 and/or SP-A1 monomers.[15]

Functions

Innate immunity

The role of SFTPA2 in innate immunity has been extensively studied. SP-A has the ability to bind and agglutinate bacteria, fungi, viruses, and other non-biological antigens. Some of the functions by which both SFTPA2 and SFTPA1 contribute to innate immunity include:

Environmental insults such as air pollution, and exposure to high concentrations of ozone and particulate matter can affect SP-A expression and function, via mechanisms that involve epigenetic regulation of SFTPA2 expression.[18]

Clinical significance

Deficiency in SP-A levels is associated with infant respiratory distress syndrome in prematurely born infants with developmental insufficiency of surfactant production and structural immaturity in the lungs.[19] Alterations of the relative levels of SP-A1 and SP-A2 have been found in BALF from patients with cystic fibrosis,[20] asthma,[21] and infection.[20]

SFTPA2 genetic variants, SNPs, haplotypes, and other genetic variations have been associated with acute and chronic lung disease in several populations of neonates, children, and adults.[7] SFTPA2 mutations also associated with pulmonary fibrosis via mechanisms that involve protein instability and endoplasmic reticulum stress.[22] Methylation of SFTPA2 and SFTPA1 promoter sequences has also been found in lung cancer tissue.[23] [24]

SFTPA2 mRNA transcript variants

Variant id 5’UTR splice Coding 3’UTR sequence GenBank id
ABD1A ABD 1A 1A HQ021432
ABD1A0 ABD 1A0 1A0 HQ021421
ABD1A1 ABD 1A1 1A1 HQ021422
ABD1A2 ABD 1A2 1A2 HQ021423
ABD1A3 ABD 1A3 1A3 HQ021424
ABD1A5 ABD 1A5 1A5 HQ021425
ABD'1A ABD' 1A 1A HQ021426
ABD'1A0 ABD' 1A0 1A0 HQ021427
ABD'1A1 ABD' 1A1 1A1 HQ021428
ABD'1A2 ABD' 1A2 1A2 HQ021429
ABD'1A3 ABD' 1A3 1A3 HQ021430
ABD'1A5 ABD' 1A5 1A5 HQ021431
SFTPA2 ABD’ 1A2 1A0 NM_001098668.2

Gene regulation

Gene expression of SFTPA2 is regulated at different levels including gene transcription, post-transcriptional processing, stability and translation (biology) of mature mRNA.[2] One of the important features of human surfactant protein A mRNAs is that they have a variable five prime untranslated region (5’UTR) generated from splicing variation of exons A, B, C, and D.[25] [26] At least 10 forms of human SFTPA2 and SFTPA1 5’UTRs have been identified that differ in nucleotide sequence, length, and relative amount.[27] Most SFTPA2 specific 5’UTRs include exon B. This 30-nucleotide long sequence has been shown to enhance both gene transcription and protein translation (biology), and plays a key role in the differential regulation of SFTPA2 and SFTPA1 expression.[28] Both ABD and ABD’ are the most represented forms among SFTPA2 transcripts (~49% each), and experimental work has shown that this sequence can stabilize mRNA, enhance translation, and activate cap-independent eukaryotic translation.[29] [30] [31] [32] Exon B of SFTPA2 also binds specific proteins (e.g. 14-3-3) that may enhance translation, in a sequence- and secondary structure- specific way. While differences at the 5’UTR are shown to regulate both transcription and translation, polymorphisms at the 3’UTR of SP-A2 variants are shown to primarily, differentially affect translation efficiency via mechanisms that involve binding of proteins [33] and/or [microRNAs]. The impact of this regulation on SFTPA2 relative protein levels may contribute to individual differences in susceptibility to lung disease.Environmental insults and pollutants also affect SFTPA2 expression. Exposure of lung cells to particulate matter affects splicing of 5’UTR exons of SFTPA2 transcripts. Pollutants and viral infections also affect SFTPA2 translation mechanisms (see eukaryotic translation, translation (biology)).[34]

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: SFTPA2 surfactant, pulmonary-associated protein A2.
  2. Silveyra P, Floros J . Genetic complexity of the human surfactant-associated proteins SP-A1 and SP-A2 . Gene . 531 . 2 . 126–32 . December 2013 . 23069847 . 3570704 . 10.1016/j.gene.2012.09.111 .
  3. Perez-Gil J, Weaver TE . Pulmonary surfactant pathophysiology: current models and open questions . Physiology . 25 . 3 . 132–41 . June 2010 . 20551227 . 10.1152/physiol.00006.2010 .
  4. Crouch EC . Erika Crouch. Collectins and pulmonary host defense . American Journal of Respiratory Cell and Molecular Biology . 19 . 2 . 177–201 . August 1998 . 9698590 . 10.1165/ajrcmb.19.2.140 .
  5. Crouch E, Hartshorn K, Ofek I . Collectins and pulmonary innate immunity . Immunological Reviews . 173 . 52–65 . February 2000 . 10719667 . 10.1034/j.1600-065x.2000.917311.x . 22948014 .
  6. Phelps DS . Surfactant regulation of host defense function in the lung: a question of balance . Pediatric Pathology & Molecular Medicine . 20 . 4 . 269–92 . 2001 . 11486734 . 10.1080/15513810109168822 . 19109567 .
  7. Silveyra P, Floros J . Genetic variant associations of human SP-A and SP-D with acute and chronic lung injury . Frontiers in Bioscience . 17 . 407–29 . 2012 . 2 . 22201752 . 3635489 . 10.2741/3935 .
  8. Floros J, Kala P . Surfactant proteins: molecular genetics of neonatal pulmonary diseases . Annual Review of Physiology . 60 . 365–84 . 1998 . 9558469 . 10.1146/annurev.physiol.60.1.365 .
  9. Floros J, Wang G . A point of view: quantitative and qualitative imbalance in disease pathogenesis; pulmonary surfactant protein A genetic variants as a model . Comparative Biochemistry and Physiology A . 129 . 1 . 295–303 . May 2001 . 11369553 . 10.1016/S1095-6433(01)00325-7 .
  10. Whitsett JA, Wert SE, Weaver TE . Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease . Annual Review of Medicine . 61 . 105–19 . 2010 . 19824815 . 10.1146/annurev.med.60.041807.123500 . 4127631 .
  11. Madsen J, Tornoe I, Nielsen O, Koch C, Steinhilber W, Holmskov U . Expression and localization of lung surfactant protein A in human tissues . American Journal of Respiratory Cell and Molecular Biology . 29 . 5 . 591–7 . November 2003 . 12777246 . 10.1165/rcmb.2002-0274OC . 10.1.1.321.5856 .
  12. Floros J, Hoover RR . Genetics of the hydrophilic surfactant proteins A and D . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1408 . 2–3 . 312–22 . November 1998 . 9813381 . 10.1016/S0925-4439(98)00077-5 . free .
  13. DiAngelo S, Lin Z, Wang G, Phillips S, Ramet M, Luo J, Floros J . Novel, non-radioactive, simple and multiplex PCR-cRFLP methods for genotyping human SP-A and SP-D marker alleles . Disease Markers . 15 . 4 . 269–81 . December 1999 . 10689550 . 3851098 . 10.1155/1999/961430 . free .
  14. Silveyra P, Floros J . Air pollution and epigenetics: effects on SP-A and innate host defence in the lung . Swiss Medical Weekly . 142 . w13579 . 2012 . 22553125 . 3601480 . 10.4414/smw.2012.13579 .
  15. Floros J, Wang G, Mikerov AN . Genetic complexity of the human innate host defense molecules, surfactant protein A1 (SP-A1) and SP-A2—impact on function . Critical Reviews in Eukaryotic Gene Expression . 19 . 2 . 125–37 . 2009 . 19392648 . 2967201 . 10.1615/critreveukargeneexpr.v19.i2.30 .
  16. Floros J . Wang G . Lin Z . Genetic Diversity of Human SP-A, a Molecule with Innate host Defense and Surfactant-Related Functions; Characteristics, Primary Function, and Significance . Current Pharmacogenomics . 3 . 2 . 87–95 . 2005 . 10.2174/1570160054022935 .
  17. Wang G, Myers C, Mikerov A, Floros J . Effect of cysteine 85 on biochemical properties and biological function of human surfactant protein A variants . Biochemistry . 46 . 28 . 8425–35 . July 2007 . 17580966 . 2531219 . 10.1021/bi7004569 .
  18. Silveyra P, Floros J . Air pollution and epigenetics: effects on SP-A and innate host defence in the lung . Swiss Medical Weekly . 142 . w13579 . 2012 . 22553125 . 3601480 . 10.4414/smw.2012.13579 .
  19. deMello DE, Heyman S, Phelps DS, Floros J . Immunogold localization of SP-A in lungs of infants dying from respiratory distress syndrome . The American Journal of Pathology . 142 . 5 . 1631–40 . May 1993 . 8494055 . 1886897 .
  20. Tagaram HR, Wang G, Umstead TM, Mikerov AN, Thomas NJ, Graff GR, Hess JC, Thomassen MJ, Kavuru MS, Phelps DS, Floros J . Characterization of a human surfactant protein A1 (SP-A1) gene-specific antibody; SP-A1 content variation among individuals of varying age and pulmonary health . American Journal of Physiology. Lung Cellular and Molecular Physiology . 292 . 5 . L1052–63 . May 2007 . 17189324 . 10.1152/ajplung.00249.2006 . 21421799 .
  21. Wang Y, Voelker DR, Lugogo NL, Wang G, Floros J, Ingram JL, Chu HW, Church TD, Kandasamy P, Fertel D, Wright JR, Kraft M . Surfactant protein A is defective in abrogating inflammation in asthma . American Journal of Physiology. Lung Cellular and Molecular Physiology . 301 . 4 . L598–606 . October 2011 . 21784968 . 3191759 . 10.1152/ajplung.00381.2010 .
  22. Maitra M, Wang Y, Gerard RD, Mendelson CR, Garcia CK . Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress . The Journal of Biological Chemistry . 285 . 29 . 22103–13 . July 2010 . 20466729 . 2903395 . 10.1074/jbc.M110.121467 . free .
  23. Vaid M, Floros J . Surfactant protein DNA methylation: a new entrant in the field of lung cancer diagnostics? (Review) . Oncology Reports . 21 . 1 . 3–11 . January 2009 . 19082436 . 2899699 . 10.3892/or_00000182 .
  24. Lin Z, Thomas NJ, Bibikova M, Seifart C, Wang Y, Guo X, Wang G, Vollmer E, Goldmann T, Garcia EW, Zhou L, Fan JB, Floros J . DNA methylation markers of surfactant proteins in lung cancer . International Journal of Oncology . 31 . 1 . 181–91 . July 2007 . 17549420 . 10.3892/ijo.31.1.181 . free .
  25. Karinch AM, Deiter G, Ballard PL, Floros J . Regulation of expression of human SP-A1 and SP-A2 genes in fetal lung explant culture . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1398 . 2 . 192–202 . June 1998 . 9689918 . 10.1016/S0167-4781(98)00047-5 . free .
  26. Karinch AM, Floros J . Translation in vivo of 5' untranslated-region splice variants of human surfactant protein-A . The Biochemical Journal . 307 . Pt 2 . 327–30 . April 1995 . 7733864 . 1136651 . 10.1042/bj3070327 .
  27. Karinch AM, Floros J . 5' splicing and allelic variants of the human pulmonary surfactant protein A genes . American Journal of Respiratory Cell and Molecular Biology . 12 . 1 . 77–88 . January 1995 . 7811473 . 10.1165/ajrcmb.12.1.7811473 .
  28. Silveyra P, Raval M, Simmons B, Diangelo S, Wang G, Floros J . The untranslated exon B of human surfactant protein A2 mRNAs is an enhancer for transcription and translation . American Journal of Physiology. Lung Cellular and Molecular Physiology . 301 . 5 . L795–803 . November 2011 . 21840962 . 3290452 . 10.1152/ajplung.00439.2010 .
  29. Wang G, Guo X, Silveyra P, Kimball SR, Floros J . Cap-independent translation of human SP-A 5'-UTR variants: a double-loop structure and cis-element contribution . American Journal of Physiology. Lung Cellular and Molecular Physiology . 296 . 4 . L635–47 . April 2009 . 19181744 . 2670766 . 10.1152/ajplung.90508.2008 .
  30. Silveyra P, Wang G, Floros J . Human SP-A1 (SFTPA1) variant-specific 3' UTRs and poly(A) tail differentially affect the in vitro translation of a reporter gene . American Journal of Physiology. Lung Cellular and Molecular Physiology . 299 . 4 . L523–34 . October 2010 . 20693318 . 2957414 . 10.1152/ajplung.00113.2010 .
  31. Noutsios GT, Silveyra P, Bhatti F, Floros J . Exon B of human surfactant protein A2 mRNA, alone or within its surrounding sequences, interacts with 14-3-3; role of cis-elements and secondary structure . American Journal of Physiology. Lung Cellular and Molecular Physiology . 304 . 11 . L722–35 . June 2013 . 23525782 . 3680765. 10.1152/ajplung.00324.2012 .
  32. Wang G, Guo X, Floros J . Differences in the translation efficiency and mRNA stability mediated by 5'-UTR splice variants of human SP-A1 and SP-A2 genes . American Journal of Physiology. Lung Cellular and Molecular Physiology . 289 . 3 . L497–508 . September 2005 . 15894557 . 10.1152/ajplung.00100.2005 .
  33. Wang G, Guo X, Floros J . Human SP-A 3'-UTR variants mediate differential gene expression in basal levels and in response to dexamethasone . American Journal of Physiology. Lung Cellular and Molecular Physiology . 284 . 5 . L738–48 . May 2003 . 12676764 . 10.1152/ajplung.00375.2002 . 13268207 .
  34. Bruce SR, Atkins CL, Colasurdo GN, Alcorn JL . Respiratory syncytial virus infection alters surfactant protein A expression in human pulmonary epithelial cells by reducing translation efficiency . American Journal of Physiology. Lung Cellular and Molecular Physiology . 297 . 4 . L559–67 . October 2009 . 19525387 . 2770795 . 10.1152/ajplung.90507.2008 .