Secreted proteins with unknown location
There are 111 proteins which are possibly secreted or have secreted isoforms, but for which local or systemic secretion can not be determined due to lack of data, data with low reliability or conflicting data, or where the existence of a secreted form is dubious.
Functions of secreted proteins with unknown location
In Figure 1 the function of these proteins have been annotated, based mainly on Uniprot molecular function and biological process keywords, to a single function term according to 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. Other Uniprot terms to which only a few proteins were annotated were grouped under the term Other. According to these criteria, less than half (59%) of these genes encode proteins with a known function according to Uniprot keywords. The largest groups are enzymes (n= 21) including some potential phospholipases and serine proteases, and receptors (n= 11) with possibly secreted isoforms.
Tissue specificity classification
The genes were further analyzed based on mRNA expression and categorized according to tissue specificity and tissue distribution. Only 14% of the genes were classified as tissue -or group enriched, i.e. having either at least four-fold higher mRNA level in one tissue or in a group of two to five tissues compared to all other tissues. For 11 genes RNA expression was not detected in any of the analyzed samples from HPA or GTEx (Fig. 2). Regarding expression patterns across all tissues, more than half of the genes show a less tissue restricted expression and were detected in more than 30% of the tissues, with 15% being expressed in all analyzed tissues (Fig. 3).
Figure 2. Number of genes encoding proteins that are locally secreted - unknown location, categorized according to tissue specificity. Categories include: tissue enriched, defined as mRNA level in one tissue at least four-fold higher than in all other tissues; group enriched, defined as four-fold higher average mRNA level in a group of two to five tissues compared to all other tissues; tissue enhanced, defined as four-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 nTPM in all tissues; and not detected, defined as < 1 nTPM in all tissues.
Figure 3. Number of genes encoding proteins that are locally secreted - unknown location, 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 secreted proteins with unknown location
The tissue of origin according to RNAseq data for the 9 proteins found to be tissue enriched was investigated, and the result is shown in Figure 4.