Proposed model of normal and pathological processing and transport of neutrophil elastase.

The product of the ELA2 gene, neutrophil elastase (NE), is shown in the membrane of the trans Golgi network (TGN). If the C-terminus is cleaved, then NE normally interacts with AP3 (via the mu subunit of AP3 recognizing a tyrosine residue, depicted by a black dot, in the cytoplasmic tail of NE), which transports it to granules, where NE re-equilibrates into a soluble form. If the C-terminus remains intact, then interaction with AP3 is blocked and NE is routed to a default destination in the plasma and other membranes. In SCN, deletions of the AP3 recognition signal or missense mutations that favor a transmembrane configuration of NE increase trafficking through the membrane pathway. Mutations of AP3 itself, as in canine cyclic neutropenia and HPS2, act similarly. In cyclic neutropenia, mutations disrupting the transmembrane segments favor a shift in equilibrium to soluble forms accumulating in granules. Mutations of Gfi1 lead to overexpression of ELA2, overwhelming normal AP3-mediated trafficking and diverting excess NE to membranes.