Surfactant protein A1 explained

Surfactant protein A1 (SP-A1), also known as Pulmonary surfactant-associated protein A1 (PSP-A) is a protein that in humans is encoded by the SFTPA1 gene.^{[1] [2]}

Summary

SP-A1 is primarily synthesised in type II alveolar cells in the lung, 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 alveoli and prevent their collapse during expiration. The protein component of surfactant helps in the modulation of the innate immune response, and inflammatory processes.

SP-A1 is a member of a subfamily of C-type lectins called collectins. Together with SP-A2, they are the most abundant proteins of pulmonary surfactant. SP-A1 binds to the carbohydrates found in the surface of several microorganisms and helps in the defense against respiratory pathogens.^{[3] [4] [5]}

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. Changes in the amount or composition of surfactant can alter its function and are associated with respiratory diseases.^{[6] [7] [8] [9]}

SFTPA1 expression

The lung is the main site of SFTPA1 synthesis, but SFTPA1 mRNA expression has also been detected in the trachea, prostate, pancreas, thymus, colon, eye, salivary gland and other tissues.^[10] 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

SFTPA1 is located in the long arm q of chromosome 10, close to SFTPA2. The SFTPA1 gene is 4505 base pairs in length, and 94% similar to SFTPA2. The structure of SFTPA1 consists of four coding exons (I-IV), and several 5'UTR untranslated exons (A, B, B', C, C', D, D').^{[11] [12]} The expression of SFTPA1 is regulated by cellular factors including proteins, small RNAs (microRNAs), glucocorticoids, etc. Its expression is also regulated by epigenetic and environmental factors.^[13]

Differences in the SFTPA1 gene sequence at the coding region determine SP-A genetic variants or haplotypes among individuals.^[12] More than 30 variants have been identified and characterized for SFTPA1 (and SFTPA2) in the population. SFTPA1 variants result from nucleotide changes in the codons of amino acids 19, 50, 62, 133, and 219. Two of these do not modify the SP-A1 protein sequence (amino acids 62 and 133), whereas the rest result in amino acid substitutions (amino acid 19, 50, 133, and 219). Four SP-A1 variants (6A, 6A², 6A³, 6A⁴) are in higher frequency in the general population. The most frequently found variant is 6A².^{[14] [15]}

Structure

Surfactant protein A (SP-A) is a protein of 248 amino acids usually found in large oligomeric structures. The mature SP-A1 monomer is a 35kDa protein that differs from SP-A2 in four amino acids at the coding region. The structure of SP-A1 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.^{[14] [15]} The amino acid differences that distinguish between SP-A1 and SP-A2 genes and between their corresponding variants are located at the collagen-like domain. The amino acid differences that distinguish among SFTPA1 variants are located both at the carbohydrate recognition and the collagen-like domains.^{[14] [16]}

SP-A1 monomers group with other SP-A1 or SP-A2 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-A1 and/or SP-A2 monomers.^[14]

Functions

• Binding of pathogens, allergens, and other molecules
• Increasing phagocytosis and chemotaxis of alveolar macrophages
• Induction of proliferation of immune cells
• Stimulation of proinflammatory cytokine production
• Modulation of the generation of reactive oxygen species
• Serving as a hormone in parturition
• Maintaining the structure of tubular myelin (an extracellular form of surfactant)

Innate immunity

The role of SFTPA1 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 SFTPA1 and SFTPA2 contribute to innate immunity include:

• opsonization of bacteria for phagocytosis by alveolar macrophages
• recruitment of monocytes and neutrophils to the site of inflammation/infection
• enhancement of pathogen-killing mechanisms: phagocytosis, release of reactive oxygen species, release of nitric oxide
• control of cytokine production by immune cells
• transition of innate immunity to adaptive immunity (by interaction with cell surface receptors of dendritic cells to allow antigen presentation)

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 SFTPA1 expression.^[13]

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.^[17]

SFTPA1 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.^[6] Genetic variations in SFTPA1 have been associated with susceptibility to idiopathic pulmonary fibrosis, a lung disease characterized by shortness of breath, pulmonary infiltrates and inflammation that results in acute lung damage with subsequent scarring of lung tissue.^[18] Genetic variations in SFTPA1 are also a cause of susceptibility to respiratory distress syndrome in premature infants, a lung disease characterized by deficient gas exchange, diffuse atelectasis, high-permeability lung edema and fibrin-rich alveolar deposits Web site: surfactant protein A1. .The ratio of SP-A1 to total SP-A has been correlated with lung disease (e.g. asthma, cystic fibrosis) and aging.^{[19] [20]} Methylation of SFTPA1 promoter sequences has also been found in lung cancer tissue.^{[21] [22]}

SFTPA1 mRNA transcript variants

Variant id	5'UTR splice	Coding	3'UTR sequence	GenBank id
AD'6A	AD'	6A	6A	HQ021433
AD'6A^2	AD'	6A^2	6A^2	HQ021434
AD'6A^3	AD'	6A^3	6A^3	HQ021435
AD'6A^4	AD'	6A^4	6A^4	HQ021436
AB'D'6A	AB'D'	6A	6A	JX502764
AB'D'6A^2	AB'D'	6A^2	6A^2	HQ021437
AB'D'6A^3	AB'D'	6A^3	6A^3	HQ021438
AB'D'6A^4	AB'D'	6A^4	6A^4	HQ021439
ACD'6A	ACD'	6A	6A	JX502765
ACD'6A^2	ACD'	6A^2	6A^2	HQ021440
ACD'6A^3	ACD'	6A^3	6A^3	HQ021441
ACD'6A^4	ACD'	6A^4	6A^4	HQ021442
SFTPA1 variant 1	AB'D'	6A^3	6A^3	NM_005411.4
SFTPA1 variant 2	ACD'	6A^3	6A^3	NM_001093770.2
SFTPA1 variant 3	ABD'	6A^3	6A^3	NM_001164644.1
SFTPA1 variant 4	AD'	6A^3	6A^3	NM_001164647.1
SFTPA1 variant 5	ACD'	6A^3 (truncated)	6A^3	NM_001164645.1
SFTPA1 variant 6	AB'D'	6A^3 (truncated)	6A^3	NM_001164646.1

Gene regulation

Gene expression of SFTPA1 is regulated at different levels including gene transcription, post-transcriptional processing, stability and translation 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.^{[23] [24]} At least 10 forms of human SFTPA1 and SFTPA2 5'UTRs have been identified that differ in nucleotide sequence, length, and relative amount. Specific SFTPA1 or SFTPA2 5'UTRs have also been characterized. Some SFTPA1 specific 5'UTRs include exons B' or C. These two exons contain upstream AUGs (uAUGs) that can potentially act as sites for translation initiation (see eukaryotic translation), affecting protein translation and SFTPA1 relative content. The majority of SFTPA1 transcripts lack exon B, a sequence implicated in transcription and translation enhancement, indicating a differential regulation of SFTPA1 and SFTPA2 expression.^[25] The AD' form is the most represented among SFTPA1 transcripts (81%),^[26] and experimental work has shown that this sequence can stabilize mRNA and enhance translation, but the mechanisms implicated in this regulation are still under investigation.^{[27] [28] [29]} While differences at the 5'UTR are shown to regulate both transcription and translation,^[25] polymorphisms at the 3'UTR of SP-A1 variants are shown to primarily, differentially affect translation efficiency^[28] via mechanisms that involve binding of proteins^[30] and/or [microRNAs].^[28] The impact of this regulation on SFTPA1 and SFTPA2 protein levels may contribute to individual differences in susceptibility to lung disease.Environmental insults and pollutants also affect SFTPA1 expression. Exposure of lung cells to particulate matter affects splicing of 5'UTR exons of SFTPA1 transcripts. Pollutants and viral infections also affect SFTPA1 translation mechanisms (see eukaryotic translation, translation (biology)).^{[27] [31]}

Further reading

• Lu J . Collectins: collectors of microorganisms for the innate immune system . BioEssays . 19 . 6 . 509–18 . Jun 1997 . 9204768 . 10.1002/bies.950190610 . 23565862 .
• 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 . Nov 1998 . 9813381 . 10.1016/S0925-4439(98)00077-5 . free .
• Khubchandani KR, Snyder JM . Surfactant protein A (SP-A): the alveolus and beyond . FASEB Journal . 15 . 1 . 59–69 . Jan 2001 . 11149893 . 10.1096/fj.00-0318rev . free . 10.1.1.326.5508 . 1934315 .
• Katyal SL, Singh G, Locker J . Characterization of a second human pulmonary surfactant-associated protein SP-A gene . American Journal of Respiratory Cell and Molecular Biology . 6 . 4 . 446–52 . Apr 1992 . 1372511 . 10.1165/ajrcmb/6.4.446 .
• Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T . Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids . The Journal of Biological Chemistry . 267 . 14 . 9972–9 . May 1992 . 10.1016/S0021-9258(19)50187-9 . 1577827 . free .
• Endo H, Oka T . An immunohistochemical study of bronchial cells producing surfactant protein A in the developing human fetal lung . Early Human Development . 25 . 3 . 149–56 . Jun 1991 . 1935736 . 10.1016/0378-3782(91)90111-F .
• Voss T, Melchers K, Scheirle G, Schäfer KP . Structural comparison of recombinant pulmonary surfactant protein SP-A derived from two human coding sequences: implications for the chain composition of natural human SP-A . American Journal of Respiratory Cell and Molecular Biology . 4 . 1 . 88–94 . Jan 1991 . 1986781 . 10.1165/ajrcmb/4.1.88 .
• Haagsman HP, White RT, Schilling J, Lau K, Benson BJ, Golden J, Hawgood S, Clements JA . Studies of the structure of lung surfactant protein SP-A . The American Journal of Physiology . 257 . 6 Pt 1 . L421–9 . Dec 1989 . 2610270 . 10.1152/ajplung.1989.257.6.L421.
• Fisher JH, Kao FT, Jones C, White RT, Benson BJ, Mason RJ . The coding sequence for the 32,000-dalton pulmonary surfactant-associated protein A is located on chromosome 10 and identifies two separate restriction-fragment-length polymorphisms . American Journal of Human Genetics . 40 . 6 . 503–11 . Jun 1987 . 2884868 . 1684155 .
• White RT, Damm D, Miller J, Spratt K, Schilling J, Hawgood S, Benson B, Cordell B . Isolation and characterization of the human pulmonary surfactant apoprotein gene . Nature . 317 . 6035 . 361–3 . 1985 . 2995821 . 10.1038/317361a0 . 1985Natur.317..361W . 4357498 .
• Floros J, Steinbrink R, Jacobs K, Phelps D, Kriz R, Recny M, Sultzman L, Jones S, Taeusch HW, Frank HA . Isolation and characterization of cDNA clones for the 35-kDa pulmonary surfactant-associated protein . The Journal of Biological Chemistry . 261 . 19 . 9029–33 . Jul 1986 . 10.1016/S0021-9258(19)84483-6 . 3755136 . free .
• Schaeffer E, Guillou F, Part D, Zakin MM . A different combination of transcription factors modulates the expression of the human transferrin promoter in liver and Sertoli cells . The Journal of Biological Chemistry . 268 . 31 . 23399–408 . Nov 1993 . 10.1016/S0021-9258(19)49476-3 . 8226864 . free .
• Khoor A, Gray ME, Hull WM, Whitsett JA, Stahlman MT . Developmental expression of SP-A and SP-A mRNA in the proximal and distal respiratory epithelium in the human fetus and newborn . The Journal of Histochemistry and Cytochemistry . 41 . 9 . 1311–9 . Sep 1993 . 8354874 . 10.1177/41.9.8354874 . free .
• Strayer DS, Yang S, Jerng HH . Surfactant protein A-binding proteins. Characterization and structures . The Journal of Biological Chemistry . 268 . 25 . 18679–84 . Sep 1993 . 10.1016/S0021-9258(17)46683-X . 8360162 . free .
• Kölble K, Lu J, Mole SE, Kaluz S, Reid KB . Assignment of the human pulmonary surfactant protein D gene (SFTP4) to 10q22-q23 close to the surfactant protein A gene cluster . Genomics . 17 . 2 . 294–8 . Aug 1993 . 8406480 . 10.1006/geno.1993.1324 .
• 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 .
• Chroneos ZC, Abdolrasulnia R, Whitsett JA, Rice WR, Shepherd VL . Purification of a cell-surface receptor for surfactant protein A . The Journal of Biological Chemistry . 271 . 27 . 16375–83 . Jul 1996 . 8663107 . 10.1074/jbc.271.27.16375 . free .
• Planer BC, Ning Y, Kumar SA, Ballard PL . Transcriptional regulation of surfactant proteins SP-A and SP-B by phorbol ester . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1353 . 2 . 171–9 . Aug 1997 . 9294011 . 10.1016/S0167-4781(97)00070-5 . free .

Notes and References

1. Web site: Entrez Gene: Surfactant protein A1 .
2. Silveyra P, Floros J . Genetic complexity of the human surfactant-associated proteins SP-A1 and SP-A2 . Gene . 531 . 2 . 126–32 . Dec 2013 . 23069847 . 3570704 . 10.1016/j.gene.2012.09.111 .
3. Crouch EC . Erika Crouch. Collectins and pulmonary host defense . American Journal of Respiratory Cell and Molecular Biology . 19 . 2 . 177–201 . Aug 1998 . 9698590 . 10.1165/ajrcmb.19.2.140 .
4. Crouch E, Hartshorn K, Ofek I . Collectins and pulmonary innate immunity . Immunological Reviews . 173 . 52–65 . Feb 2000 . 10719667 . 10.1034/j.1600-065x.2000.917311.x . 22948014 .
5. 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 .
6. 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 . 10.2741/3935 . 3635489.
7. 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 .
8. 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 .
9. 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 .
10. 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 . Nov 2003 . 12777246 . 10.1165/rcmb.2002-0274OC . 10.1.1.321.5856 .
11. 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 . Nov 1998 . 9813381 . 10.1016/S0925-4439(98)00077-5 . free .
12. 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 . Dec 1999 . 10689550 . 3851098 . 10.1155/1999/961430 . free .
13. 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 .
14. 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 .
15. ingentaconnect Genetic Diversity of Human SP-A, a Molecule with Innate host Defe... . Current Pharmacogenomics . June 2005 . 3 . 2 . 87–95 . 10.2174/1570160054022935 . Floros . Joanna . Wang . Guirong . Lin . Zhenwu .
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17. 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 .
18. Selman M, King TE, Pardo A . Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy . Annals of Internal Medicine . 134 . 2 . 136–51 . Jan 2001 . 11177318 . 10.7326/0003-4819-134-2-200101160-00015 . 10955241 .
19. 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 .
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21. 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 . Jan 2009 . 19082436 . 2899699 . 10.3892/or_00000182 .
22. 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 . Jul 2007 . 17549420 . 10.3892/ijo.31.1.181 . free .
23. 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 . Jun 1998 . 9689918 . 10.1016/S0167-4781(98)00047-5 . free .
24. Karinch AM, Floros J . Translation in vivo of 5' untranslated-region splice variants of human surfactant protein-A . The Biochemical Journal . 307 . 2 . 327–30 . Apr 1995 . 7733864 . 1136651 . 10.1042/bj3070327.
25. 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 . Nov 2011 . 21840962 . 3290452 . 10.1152/ajplung.00439.2010 .
26. 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 . Jan 1995 . 7811473 . 10.1165/ajrcmb.12.1.7811473 .
27. 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 . Apr 2009 . 19181744 . 2670766 . 10.1152/ajplung.90508.2008 .
28. 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 . Oct 2010 . 20693318 . 2957414 . 10.1152/ajplung.00113.2010 .
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30. 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 .
31. 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 . Oct 2009 . 19525387 . 2770795 . 10.1152/ajplung.90507.2008 .