Proteins locally secreted in other tissues
In addition to the proteins categorized as locally secreted in the brain, digestive system, extracellular matrix, female and male reproductive systems, another 250 proteins were annotated as secreted in various other tissue types based on manual literature analysis and data analysis. Here, we have grouped these proteins into a category called ‘Other tissues’. This category includes proteins locally secreted in specific tissues, such as skin, lung and eye, or locally secreted by cell types found in a wide range of tissues, such as epithelial cells and endothelial cells.
Functions of proteins locally secreted in other tissues
All secreted proteins were classified according to function based on Uniprot molecular function and biological processes keywords. The annotations were prioritized in the following hierarchy: Blood coagulation, Complement pathway, Acute phase, Cytokine, Hormone, Neuropeptide, Growth factor, Receptor, Lectin, Transport, Developmental protein, Defence, Enzyme, Enzyme inhibitor, Transcription, Immunity, Cell adhesion. Each protein was assigned one function.
The results of the analysis are presented in Figure 1. It was found that 43 proteins locally secreted in Other tissues are various enzymes with diverse functions ranging from antibacterial activities to cell signaling and maintenance of body homeostasis. Furthermore, 23 proteins were characterized as different growth factors regulating processes such as nerve growth and bone formation, and 20 proteins were shown to be active during embryogenesis and normal cell development. The remaining proteins were categorized as enzyme inhibitors (n=12), various cytokines (n=10), receptors (n=10), hormones (n= 9), transport proteins (n=8), proteins involved in first line of defense against pathogens (n=8), proteins involved in immunity (n=6), different neuropeptides (n=5), and proteins involved in transcription (n=1). 64 proteins lacked an annotated function.
Figure 1. Number of proteins that are locally secreted in tissues in the category denoted as other tissues, categorized according to function. Annotation was based on Uniprot molecular function and biological processes keywords. Each bar is clickable and gives a search result of proteins that belong to the selected category.
Tissue specificity and tissue distribution classification
The genes were further analyzed with regard to mRNA expression and categorized according to tissue specificity and tissue distribution. More than a third of all genes showed either tissue enriched (n=37) or group enriched (n=54) mRNA expression, i.e. either at least five-fold higher mRNA level in one tissue or in a group of two to five tissues compared to all other tissues (Figure 2). Approximately half of the genes showed tissue enhanced (n=127) mRNA expression, i.e. five-fold higher average mRNA levels in one or more tissues compared to the mean mRNA level. Around 12% (n=31) had low tissue specificity and was detected in over 30 percent of the analyzed tissues. A few genes (n=1) could not be detected in any tissue.
Figure 2. Number of genes encoding proteins that are locally secreted in other tissues, categorized according to tissue specificity. Categories include: tissue enriched, defined as mRNA level in one tissue at least five-fold higher than in all other tissues; group enriched, defined as five-fold higher average mRNA level in a group of two to five tissues compared to all other tissues; tissue enhanced, defined as five-fold higher average mRNA level in one or more tissues compared to the mean mRNA level of all tissues; expressed in all, defined as ≥ 1 NX in all tissues; and not detected, defined as < 1 NX in all tissues.
For the vast majority of genes, mRNA was detected in more than one tissue (Figure 3). For a few genes (n=3), mRNA was detected in a single tissue.
Figure 3. Number of genes encoding proteins that are locally secreted in other tissues, categorized according to tissue distribution. Categories include: detected in all, defined as n=100%; detected in many, defined as 31%=< n <100%; detected in some, defined as 1< n <31%; detected in single defined as single n=1; and not detected, n=0.
Origin of proteins secreted in other tissues
The analysis of gene expression showed that most proteins annotated as locally secreted in the Other tissues category are produced in the lung (n=9), retina (n=8) and skin (n=7) (Figure 4). Remaining proteins were encoded by genes with mRNA enriched in brain (n=3), tongue (n=2), placenta (n=2), esophagus (n=1), heart muscle (n=1), kidney (n=1), lymphoid tissue (n=1), skeletal muscle (n=1) and thyroid gland (n=1).
It should be noted that proteins specific to certain tissue types not available to the Human Protein Atlas project might appear as being enriched in tissues different from what is expected. One example is Ameloblastin (AMBN), a protein suggested to play a role in tooth mineralization, which due to lack of dental tissue was found to have highest mRNA levels in the brain.
Figure 4. Number of tissue enriched genes encoding proteins that are locally secreted in Other tissues, according to the tissue with highest mRNA level. Each bar is clickable and gives a search result of proteins that belong to the selected category.
Examples of proteins locally secreted in other tissues
Pulmonary surfactants constitute a mixture of lipids and proteins synthesized and secreted by type II pneumocytes (type II alveolar cells) into the alveolar space. The main function of the surfactants is to reduce the surface tension at the air-liquid interface as the gas exchange takes place between alveoli and the bloodstream. Surfactant protein B (SFTPB) is an example of a surface-active lipoprotein essential for normal respiratory function and homeostasis after birth. Another example is surfactant protein A1 (SFTPA1) that, in addition to maintaining surfactant homeostasis, also takes part in the defense against respiratory pathogens by binding specific carbohydrate moieties on the surface of invading microorganisms.
The retinal interphotoreceptor matrix is a specialized extracellular material in the subretinal space, surrounding the photoreceptor inner and outer segments, where key reactions such as vitamin A trafficking, segment stability and adhesion takes place. One of the major components of the retinal interphotoreceptor matrix is interphotoreceptor matrix proteoglycan 1 (IMPG1) which is thought to be involved in adhesion of the neural retina to the retinal pigment epithelium and in maintaining the viability of photoreceptor cells. Another secreted protein found in the interphotoreceptor matrix is retinol binding protein 3 (RBP3), a large glycoprotein known to bind retinoids. RBP3 is suggested to shuttle retinoids between the retinal pigment epithelium and the visual pigments in the photoreceptor cells, which is a critical part of the visual process.
Opticin (OPTC) is synthesized by the nonpigmented ciliary epithelium and secreted into the vitreous of the eye, where it binds collagen fibrils essential to the gel structure of the vitreous.
The thyroid gland is an endocrine organ regulating metabolism and blood calcium levels. Elevated thyroid stimulating hormone (TSH) levels stimulate the thyroid follicular cells to produce the thyroid hormone precursor thyroglobulin (TG). Thyroglobulin is secreted into the follicular lumen, where it is stored awaiting iodination in order to form the active thyroid hormones thyroxine (T4) and triiodothyronine (T3).
The skin is our largest organ acting as a first line of defense against invading pathogens and serves as protective barrier against the outer environment. Dermokine (DMKN) is a protein found in the differentiated layers of skin where it may act as a regulator of keratinocyte differentiation. It has also been found to be expressed in many other epithelial tissues and to be differentially upregulated in inflammatory diseases.
Another example is cytastatin M/E (CST6), a protein mainly restricted to the epithelial layers of the skin in hair follicles, sweat glands, sebaceous glands and the granular layer of epidermis, where it has been suggested to play a regulatory role in epidermal differentiation by regulating the crosslinking and desquamation of the cornified layer of the skin.
Relevant links and publications