SFTPA2

Summary

The protein encoded by this gene (SP-A2) is primarily synthesized in lung alveolar type II cells (see type II pneumocyte), 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.

SP-A2 is a member of a subfamily of C-type lectins called collectins. Together with SP-A1 (see SFTPA1), 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.

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.

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. Using specific monoclonal antibodies for Surfactant protein A, the protein can be detected in lung alveolar type II pneumocytes, Clara 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’). 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.

Differences in the SFTPA2 gene sequence at the coding region determine SP-A genetic variants or haplotypes among individuals. 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.

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. 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.

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.

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.

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. Alterations of the relative levels of SP-A1 and SP-A2 have been found in BALF from patients with cystic fibrosis, asthma, and infection.

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. Mutations in the SFTPA2 gene are found in patients with interstitial lung disease and lung cancer. SFTPA2 mutations also associated with pulmonary fibrosis via mechanisms that involve protein instability and endoplasmic reticulum stress. Methylation of SFTPA2 and SFTPA1 promoter sequences has also been found in lung cancer tissue.

Gene regulation

Gene expression of SFTPA2 is regulated at different levels including gene transcription, post-transcriptional processing, stability and translation (biology) of mature mRNA. 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. At least 10 forms of human SFTPA2 and SFTPA1 5’UTRs have been identified that differ in nucleotide sequence, length, and relative amount. 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. 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. 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 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)).