Over one third of all known proteolytic enzymes are serine proteases. Among these, the trypsin-like serine proteases comprise one of the best characterized subfamilies due to their essential roles in blood coagulation, food digestion, fibrinolysis, or immunity. Trypsin-like serine proteases possess primary substrate specificity for basic amino acids. Most of the well-characterized trypsin-like proteases such as trypsin, plasmin, or urokinase are soluble proteases that are secreted into the extracellular environment. At the turn of the millennium, a number of novel trypsin-like serine proteases have been identified that are anchored in the cell membrane, either by a transmembrane domain at the N- or C-terminus or via a glycosylphosphatidylinositol (GPI) linkage. Meanwhile more than 20 membrane-anchored serine proteases (MASPs) have been identified in human and mouse, and some of them have emerged as key regulators of mammalian development and homeostasis. Thus, the MASP corin and TMPRSS6/matriptase-2 have been demonstrated to be the activators of the atrial natriuretic peptide (ANP) and key regulator of hepcidin expression, respectively. Furthermore, MASPs have been recognized as host cell factors activating respiratory viruses including influenza virus as well as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses. In particular, transmembrane protease serine S1 member 2 (TMPRSS2) has been shown to be essential for proteolytic activation and consequently spread and pathogenesis of a number of influenza A viruses in mice and as a factor associated with severe influenza virus infection in humans.

This review gives an overview on the physiological functions of the fascinating and rapidly evolving group of MASPs and a summary of the current knowledge on their role in proteolytic activation of viral fusion proteins.