| SFTPA1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | SFTPA1 , COLEC4, PSAP, PSP-A, PSPA, SFTP1, SFTPA1B, SP-A, SP-A1, SPA, SPA1, surfactant protein A1, SP-A1 beta, SP-A1 delta, SP-A1 gamma, SP-A1 epsilon, ILD1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 178630 MGI: 109518 HomoloGene: 3946 GeneCards: SFTPA1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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. [5] [6]
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. [7] [8] [9]
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. [10] [11] [12] [13]
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. [14] 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. [14]
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'). [15] [16] 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. [17]
Differences in the SFTPA1 gene sequence at the coding region determine SP-A genetic variants or haplotypes among individuals. [16] 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. [18] [19]
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. [18] [19] 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. [18] [20]
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. [18]
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:
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. [17]
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. [21]
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. [10] 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. [22] 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 "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. [23] [24] Methylation of SFTPA1 promoter sequences has also been found in lung cancer tissue. [25] [26]
| Variant id | 5'UTR splice | Coding | 3'UTR sequence | GenBank id |
|---|---|---|---|---|
| AD'6A | AD' | 6A | 6A | HQ021433 |
| AD'6A2 | AD' | 6A2 | 6A2 | HQ021434 |
| AD'6A3 | AD' | 6A3 | 6A3 | HQ021435 |
| AD'6A4 | AD' | 6A4 | 6A4 | HQ021436 |
| AB'D'6A | AB'D' | 6A | 6A | JX502764 |
| AB'D'6A2 | AB'D' | 6A2 | 6A2 | HQ021437 |
| AB'D'6A3 | AB'D' | 6A3 | 6A3 | HQ021438 |
| AB'D'6A4 | AB'D' | 6A4 | 6A4 | HQ021439 |
| ACD'6A | ACD' | 6A | 6A | JX502765 |
| ACD'6A2 | ACD' | 6A2 | 6A2 | HQ021440 |
| ACD'6A3 | ACD' | 6A3 | 6A3 | HQ021441 |
| ACD'6A4 | ACD' | 6A4 | 6A4 | HQ021442 |
| SFTPA1 variant 1 | AB'D' | 6A3 | 6A3 | NM_005411.4 |
| SFTPA1 variant 2 | ACD' | 6A3 | 6A3 | NM_001093770.2 |
| SFTPA1 variant 3 | ABD' | 6A3 | 6A3 | NM_001164644.1 |
| SFTPA1 variant 4 | AD' | 6A3 | 6A3 | NM_001164647.1 |
| SFTPA1 variant 5 | ACD' | 6A3 (truncated) | 6A3 | NM_001164645.1 |
| SFTPA1 variant 6 | AB'D' | 6A3 (truncated) | 6A3 | NM_001164646.1 |
Gene expression of SFTPA1 is regulated at different levels including gene transcription, post-transcriptional processing, stability and translation 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. [27] [28] At least 10 forms of human SFTPA1 and SFTPA2 5'UTRs have been identified that differ in nucleotide sequence, length, and relative amount. [29] 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. [30] The AD' form is the most represented among SFTPA1 transcripts (81%), [29] 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. [31] [32] [33] While differences at the 5'UTR are shown to regulate both transcription and translation, [30] polymorphisms at the 3'UTR of SP-A1 variants are shown to primarily, differentially affect translation efficiency [32] via mechanisms that involve binding of proteins [34] and/or [microRNAs]. [32] The impact of this regulation on SFTPA1 and SFTPA2 protein levels may contribute to individual differences in susceptibility to lung disease. [23] [24] 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)). [31] [35]
 | 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: Joanna Floros (1 December 2013). "Genetic complexity of the human surfactant-associated proteins SP-A1 and SP-A2". Gene . 531 (2): 126–132. doi:10.1016/J.GENE.2012.09.111. PMC 3570704 . PMID 23069847. |
Gene silencing is the regulation of gene expression in a cell to prevent the expression of a certain gene. Gene silencing can occur during either transcription or translation and is often used in research. In particular, methods used to silence genes are being increasingly used to produce therapeutics to combat cancer and other diseases, such as infectious diseases and neurodegenerative disorders.
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.
Dipalmitoylphosphatidylcholine (DPPC) is a phospholipid (and a lecithin) consisting of two C16 palmitic acid groups attached to a phosphatidylcholine head-group.
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 danger-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.
BPI fold containing family A, member 1 (BPIFA1), also known as Palate, lung, and nasal epithelium clone (PLUNC), is a protein that in humans is encoded by the BPIFA1 gene. It was also formerly known as "Secretory protein in upper respiratory tracts" (SPURT). The BPIFA1 gene sequence predicts 4 transcripts ; 3 mRNA variants have been well characterized. The resulting BPIFA1 is a secreted protein, expressed at very high levels in mucosa of the airways 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 and pancreas. The protein can be detected on the apical side of epithelial cells and in airway surface liquid, nasal mucus, and sputum.
Surfactant protein D, also known as SP-D, is a lung surfactant protein part of the collagenous family of proteins 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.
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.
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.
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.
Calu-3 is a human lung cancer cell line commonly used in cancer research and drug development. Calu-3 cells are epithelial and can act as respiratory models in preclinical applications.
Precision cut lung slices or PCLS refer to thin sections of lung tissue that are prepared with high precision and are typically used for experimental purposes in the field of respiratory research. These slices are utilized to study various aspects of lung physiology, pathology, and pharmacology, providing researchers with a valuable tool for investigating lung diseases and testing the effects of drugs on lung tissue.
