ELA2

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Introductions

ELA2 is a serine protease that belongs to the same family as chymotrypsin and has broad substrate specificity. ELA2 is secreted by neutrophils during inflammation and destroys bacteria and host tissues. It also localizes to extra-neutrophilic traps (NETs) through a high affinity for DNA, an unusual property of serine proteases.

Composition

Similar with other serine proteases, it contains a charge relay system consisting of a catalytic triad of histidine, aspartate and serine residues that are dispersed in the primary sequence of the polypeptide but are clustered together in the three-dimensional conformation of the folded protein. The gene encoding ELA2, ELA2, consists of five exons. ELA2 is closely related to other cytotoxic immunoserine proteases, such as granzyme and cathepsin G, which are more distantly related to CELA1 in the digestive system.

ELA2 Family

ELA2 is a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. There are six human elastase genes encoding structurally similar elastases 1, 2, 2A, 2B, 3A, and 3B. ELA2 hydrolyzes proteins within specialized neutrophil lysosomes, called nitrogenophil granules, and proteins from the extracellular matrix after protein release from activated neutrophils.

Function

ELA2 may play a role in degenerative and inflammatory diseases through proteolysis of collagen-IV and elastin of the extracellular matrix. This protein degrades outer membrane protein A (OmpA) of Escherichia coli and pathogenic factors of bacteria such as Shigella, Salmonella and Yersinia. Mutations in this gene have been associated with circulating neutropenia (CyN) and severe congenital neutropenia (SCN). At least 95 pathogenic mutations in this gene have been identified. The gene clusters with other members of the serine protease gene family, the azo protease 1 and protease 3 genes, on chromosome 19pter. All 3 genes are expressed coordinately and their protein products are packaged together into nitrogenophil granules during neutrophil differentiation.

Inhibitors

In order to minimize damage to tissues, there are few inhibitors of ELA2. One group of inhibitors is Serine Protease Inhibitors. ELA2 has been shown to interact with Alpha 2-antiplasmin, which belongs to the serine protein family.

Clinical Significance

ELA2 is an important protease that can cause emphysema or emphysematous changes when its expression is abnormal. This involves disruption of lung structures and an increase in air pockets. mutations in the ELANE gene result in periodic and severe congenital neutropenia, a failure of neutrophils to mature. In the 2019 study, it was confirmed that ELANE deletion does not cause neutropenia.

ELA2 Selectively Kills Cancer Cells

As a key effector of innate immunity, human neutrophils (PMNs) can kill cancer cells and their therapeutic potential is being explored in clinical trials, but the mechanism by which they kill cancer cells is not fully understood. Human neutrophils release ELANE to selectively kill multiple cancer cells, ELANE protein hydrolysis releases the CD95 death domain to selectively kill cancer cells, ELANE attenuates tumor growth and induces CD8⁺ T cell-mediated off-target effects, and SLPI silences the anticancer function of ELANE in mouse neutrophils. On May 7, 2021, Lev Becker et al. of the American Society for Cancer Biology published an article in Cell, "Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis" in Cell. The article demonstrates that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) that kills many cancer cell types while preserving non-cancerous cells.