Origin and Expansion of the Serine Protease Repertoire in the Myelomonocyte Lineage

The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the multi-domain proteases of the blood coagulation and complement system. Similar to the very old digestive system, highly diverse cleavage specificities emerged in various cell lineages of the immune defense system during vertebrate evolution. The four neutrophil serine proteases (NSPs) expressed in the myelomonocyte lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, collectively display a broad repertoire of (S1) specificities. The origin of NSPs can be traced back to a circulating liver-derived trypsin-like protease, the complement factor D ancestor, whose activity is tightly controlled by substrate-induced activation and TNF alpha-induced locally upregulated protein secretion. However, the present-day descendants are produced and converted to mature enzymes in precursor cells of the bone marrow and are safely sequestered in granules of circulating neutrophils. The potential site and duration of action of these cell-associated serine proteases are tightly controlled by the recruitment and activation of neutrophils, by stimulus-dependent regulated secretion of the granules, and by various soluble inhibitors in plasma, interstitial fluids, and in the inflammatory exudate. An extraordinary dynamic range and acceleration of immediate defense responses have been achieved by exploiting the high structural plasticity of the trypsin fold.

Automated summary

The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by digestive enzymes in the gastrointestinal tract and multi-domain proteases in the blood coagulation and complement system. The immune defense system in vertebrates has developed diverse cleavage specificities similar to the ancient digestive system. Neutrophil serine proteases (NSPs) have a broad range of specificities and trace their origin back to a circulating liver-derived trypsin-like protease. These serine proteases are produced in precursor cells in the bone marrow and safely stored in granules in circulating neutrophils, with their actions tightly controlled by various factors such as recruitment and activation of neutrophils and soluble inhibitors in different body fluids. The high structural plasticity of the trypsin fold has enabled an extraordinary dynamic range and rapid defense responses.