Bioinformatics Analysis of the Subcellular Distribution of the Human Serpin Superfamily Reveals Putative Nuclear Localization and Nuclear Export Signals, Suggesting Potential Intracellular Roles of Interest

The serpin (serine protease inhibitor) superfamily is the largest class of protease inhibitors, involved in proteolytic cascades and mostly serving as serine/cysteine proteinase inhibitors. Serpins are involved in various biological functions: coagulation, fibrinolysis, angiogenesis, and have crucial roles in various diseases, including cardiac fibrosis, Alzheimer’s, emphysema, obesity, and diabetes. Based on the subcellular distribution profile, vertebrate serpins are classified as intracellular and extracellular serpins. Clade B serpins are considered ancestral serpins, mainly found inside the cells. Clade C serpins were the first to appear extracellularly and most likely bridge intracellular and extracellular serpins. Surprisingly, few reports indicated that secretory serpins such as Plasminogen activator inhibitor-1 (PAI-1) are localized in various subcellular compartments. The intracellular localization of such serpins prompted us to investigate whether the other members of the human serpin superfamily were also inside the cells. Here, we showed for the first time that various secretory serpins from clades A, D, E, H, and I are not obligatory extracellular and were also found in different subcellular compartments, such as the nucleus and centrosome. Surprisingly, secretory serpins tend to shuttle between the nucleus and the cytoplasm as they possess either a nuclear localization signal, a nuclear export signal, or both. Intriguingly, the intracellular localization of secretory serpins is not in line with the evolution-based origin of secretory serpins, suggesting that the secretory serpins acquired additional extracellular functions during evolution, in addition to the intracellular functions. These findings will help decipher the novel intracellular functions of secretory serpins.