Kallikreins are a family of proteases consisting of 15 closely related, secreted serine proteases expressed in majority of physiological fluids in the human body. The zymogen forms of pro-KLKs are activated extracellularly by the trypsin-like cleavage of their pro-peptide after either an Arg or Lys. The activating cleavage is performed either autocatalytically by the kallikrein itself (KLK2, KLK6 and KLK13), in a kallikrein activation cascade or by endogenous proteases that are yet unknown.
Since activation of pro-KLKs is a key mechanism in regulating KLK activity in tissues, we analyze activation of kallikreins by gingipains secreted by Porphyromonas gingivalis - a causative agent of paradontitis. Gingiapins account for 85% of general proteolytic and 99% of “trysin-like" activity of this bacterium and are the main virulence factors of this pathogen.
Upon incubation of pro-kallikreins KLK7, KLK8, KLK11, KLK13, KLK14 with the respective gingipain (Kgp and RgpB), the activity of KLKs has been released in a dose-dependent manner, indicating the gingipain potential to activate kallikrein zymogens. Importantly, activating cleavage occurred exactly within activation site in the profragment of each analyzed kallikren.
Dysfunctions in tissue-specific regulation of KLK activity has been linked to several pathologies, including respiratory diseases, neurodegeneration, anxiety, schizophrenia, skin-barrier dysfunction, pathological inflammation, and cancer. Therefore we assume that activation of kallikreins by gingipains destabilizes the proteolytic homeostasis within the crevice between the teeth and the gums of humans leading to a sustained host inflammatory response and possibly participating in the destructive outcome of periodontitis.