Fig. 2.

General scheme of GASPID maturation, secretion and inactivation. GASPIDs are initially synthesized as prepro-proteins with a signal and activation peptide. The signal peptide is removed during translation and translocation into the endoplasmic reticulum, leaving an inactive pro-GASPID with residual propeptide, as shown. Subsequent propeptide removal (typically by dipeptidylpeptidase I/cathepsin C) generates “activated”, mature GASPID, which is stored in a granule. Most GASPIDs have limited activity in this milieu because of low granule pH and tight packing in a matrix of uncleavable glycosaminoglycan. In response to signals appropriate for the immune cell of origin, the mature GASPID is secreted. Outside of the cell, the GASPID can remain associated with the outer surface of the plasma membrane, which sometimes affords protection from inhibition, or is secreted in a soluble, “free” form, which is more vulnerable to inactivation by extracellular anti-peptidases. Binding to a circulating inhibitor is usually irreversible, eventuating in clearance and destruction of the enzyme-inhibitor complex.