| SFTPA2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | SFTPA2 , COLEC5, PSAP, PSP-A, PSPA, SFTP1, SFTPA2B, SP-A, SPA2, SPAII, surfactant protein A2, SP-2A, ILD2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 178642; MGI: 109518; HomoloGene: 121995; GeneCards: SFTPA2; OMA:SFTPA2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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. [5] [6]
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. [7]
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. [8] [9] [10]
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. [11] [12] [13] [14]
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. [15] 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. [15]
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’). [16] [17] 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. [18]
Differences in the SFTPA2 gene sequence at the coding region determine SP-A genetic variants or haplotypes among individuals. [17] 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. [19] [20]
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. [19] [20] 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. [19] [21]
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. [19]
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. [22]
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. [23] Alterations of the relative levels of SP-A1 and SP-A2 have been found in BALF from patients with cystic fibrosis, [24] asthma, [25] and infection. [24]
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. [11] SFTPA2 mutations also associated with pulmonary fibrosis via mechanisms that involve protein instability and endoplasmic reticulum stress. [26] Methylation of SFTPA2 and SFTPA1 promoter sequences has also been found in lung cancer tissue. [27] [28]
| 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 expression of SFTPA2 is regulated at different levels including gene transcription, post-transcriptional processing, stability and translation (biology) of mature mRNA. [6] 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. [29] [30] At least 10 forms of human SFTPA2 and SFTPA1 5’UTRs have been identified that differ in nucleotide sequence, length, and relative amount. [31] 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. [32] Both ABD and ABD’ are the most represented forms among SFTPA2 transcripts (~49% each), [31] and experimental work has shown that this sequence can stabilize mRNA, enhance translation, and activate cap-independent eukaryotic translation. [33] [34] [35] [36] 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. [35] While differences at the 5’UTR are shown to regulate both transcription and translation, [32] polymorphisms at the 3’UTR of SP-A2 variants are shown to primarily, differentially affect translation efficiency [34] via mechanisms that involve binding of proteins [37] and/or [microRNAs]. [34] The impact of this regulation on SFTPA2 relative protein levels may contribute to individual differences in susceptibility to lung disease. [24] [25] 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)). [33] [38]
 | The 2013 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Patricia Silveyra; Joanna Floros (1 December 2013). "Genetic complexity of the human surfactant-associated proteins SP-A1 and SP-A2". Gene . Gene Wiki Review Series. 531 (2): 126–32. doi:10.1016/J.GENE.2012.09.111. ISSN 0378-1119. PMC 3570704 . PMID 23069847. Wikidata Q24621202. |
Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by type II alveolar cells. The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions. By adsorbing to the air-water interface of alveoli, with hydrophilic head groups in the water and the hydrophobic tails facing towards the air, the main lipid component of surfactant, dipalmitoylphosphatidylcholine (DPPC), reduces surface tension.
Telokin is an abundant protein found in smooth-muscle. It is identical to the C-terminus of myosin light-chain kinase. Telokin may play a role in the stabilization of unphosphorylated smooth-muscle myosin filaments. Because of its origin as the C-terminal end of smooth muscle myosin light chain kinase, it is called "telokin".
Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids that are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis, or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.
Surfactant protein D, also known as SP-D, is a lung surfactant protein part of the collagenous family of lectins called collectin. In humans, SP-D is encoded by the SFTPD gene and is part of the innate immune system. Each SP-D subunit is composed of an N-terminal domain, a collagenous region, a nucleating neck region, and a C-terminal lectin domain. Three of these subunits assemble to form a homotrimer, which further assemble into a tetrameric complex.
Surfactant protein A is an innate immune system collectin. It is water-soluble and has collagen-like domains similar to SP-D. It is part of the innate immune system and is used to opsonize bacterial cells in the alveoli marking them for phagocytosis by alveolar macrophages. SP-A may also play a role in negative feedback limiting the secretion of pulmonary surfactant. SP-A is not required for pulmonary surfactant to function but does confer immune effects to the organism.
Surfactant protein B is an essential lipid-associated protein found in pulmonary surfactant. Without it, the lung would not be able to inflate after a deep breath out. It rearranges lipid molecules in the fluid lining the lung so that tiny air sacs in the lung, called alveoli, can more easily inflate.
Surfactant protein C (SP-C), is one of the pulmonary surfactant proteins. In humans this is encoded by the SFTPC gene.
14-3-3 protein zeta/delta (14-3-3ζ) is a protein that in humans is encoded by the YWHAZ gene on chromosome 8. The protein encoded by this gene is a member of the 14-3-3 protein family and a central hub protein for many signal transduction pathways. 14-3-3ζ is a major regulator of apoptotic pathways critical to cell survival and plays a key role in a number of cancers and neurodegenerative diseases.
The sodium-hydrogen antiporter 1 (NHE-1) also known as sodium/hydrogen exchanger 1 or SLC9A1 is an isoform of sodium–hydrogen antiporter that in humans is encoded by the SLC9A1 gene.
Multidrug resistance-associated protein 1 (MRP1) is a protein that in humans is encoded by the ABCC1 gene.
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.
P2Y purinoceptor 6 is a protein that in humans is encoded by the P2RY6 gene.
NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 gene.
Fos-related antigen 1 (FRA1) is a protein that in humans is encoded by the FOSL1 gene.
Lipid phosphate phosphohydrolase 2 is an enzyme that in humans is encoded by the PPAP2C gene.
Prostasin is a protein that in humans is encoded by the PRSS8 gene.
Protein sprouty homolog 4 is a protein that in humans is encoded by the SPRY4 gene.
Surfactant metabolism dysfunction is a condition where pulmonary surfactant is insufficient for adequate respiration. Surface tension at the liquid-air interphase in the alveoli makes the air sacs prone to collapsing post expiration. This is due to the fact that water molecules in the liquid-air surface of alveoli are more attracted to one another than they are to molecules in the air. For sphere-like structures like alveoli, water molecules line the inner walls of the air sacs and stick tightly together through hydrogen bonds. These intermolecular forces put great restraint on the inner walls of the air sac, tighten the surface all together, and unyielding to stretch for inhalation. Thus, without something to alleviate this surface tension, alveoli can collapse and cannot be filled up again. Surfactant is essential mixture that is released into the air-facing surface of inner walls of air sacs to lessen the strength of surface tension. This mixture inserts itself among water molecules and breaks up hydrogen bonds that hold the tension. Multiple lung diseases, like ISD or RDS, in newborns and late-onsets cases have been linked to dysfunction of surfactant metabolism.
Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene. It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis. FOXJ1 is expressed in ciliated cells of the lung, choroid plexus, reproductive tract, embryonic kidney and pre-somite embryo stage.
Erika Crouch is a professor of pathology and the Carol B. and Jerome T. Loeb Professor of Medical Education at Washington University in St. Louis.
