Neutrophil elastase

Neutrophil elastase (EC 3.4.21.37, leukocyte elastase, ELANE, ELA2, elastase 2, neutrophil, elaszym, serine elastase, subtype human leukocyte elastase (HLE)) is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Secreted by neutrophils and macrophages during inflammation, it destroys bacteria and host tissue.[5] It also localizes to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.[6]

ELANE
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1B0F, 1H1B, 1HNE, 1PPF, 1PPG, 2RG3, 2Z7F, 3Q76, 3Q77, 4NZL, 4WVP, 5A09, 5A0A, 5A0B, 5A0C, 5ABW
Identifiers
Aliases	ELANE, ELA2, GE, HLE, HNE, NE, PMN-E, SCN1, elastase, neutrophil expressed
External IDs	OMIM: 130130 MGI: 2679229 HomoloGene: 20455 GeneCards: ELANE
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.3 Start 851,014 bp[1] End 856,247 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 C1|10 39.72 cM Start 79,886,247 bp[2] End 79,888,215 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0001106 transcription corepressor activity • heparin binding • endopeptidase activity • protease binding • peptidase activity • GO:0001948 protein binding • serine-type peptidase activity • hydrolase activity • cytokine binding • serine-type endopeptidase activity Cellular component • cytoplasm • transcriptional repressor complex • secretory granule • extracellular region • cell surface • extracellular exosome • extracellular • azurophil granule lumen • specific granule lumen • collagen-containing extracellular matrix Biological process • response to yeast • positive regulation of MAP kinase activity • negative regulation of chemotaxis • cellular calcium ion homeostasis • extracellular matrix disassembly • acute inflammatory response to antigenic stimulus • negative regulation of transcription from RNA polymerase II promoter • negative regulation of interleukin-8 biosynthetic process • defense response to fungus • proteolysis • response to lipopolysaccharide • positive regulation of immune response • protein catabolic process • defense response to bacterium • phagocytosis • neutrophil mediated killing of fungus • negative regulation of chemokine biosynthetic process • positive regulation of interleukin-8 biosynthetic process • negative regulation of inflammatory response • response to UV • leukocyte migration • positive regulation of smooth muscle cell proliferation • leukocyte migration involved in inflammatory response • positive regulation of leukocyte tethering or rolling • antimicrobial humoral response • neutrophil degranulation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1991	50701
Ensembl	ENSG00000277571 ENSG00000197561	ENSMUSG00000020125
UniProt	P08246	Q3UP87
RefSeq (mRNA)	NM_001972	NM_015779
RefSeq (protein)	NP_001963	NP_056594
Location (UCSC)	Chr 19: 0.85 – 0.86 Mb	Chr 10: 79.89 – 79.89 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

As with other serine proteinases it contains a charge relay system composed of the catalytic triad of histidine, aspartate, and serine residues that are dispersed throughout the primary sequence of the polypeptide but that are brought together in the three dimensional conformation of the folded protein. The gene encoding neutrophil elastase, ELA2, consists of five exons. Neutrophil elastase is closely related to other cytotoxic immune serine proteases, such as the granzymes and cathepsin G. It is more distantly related to the digestive CELA1.[6]

The neutrophil form of elastase (EC 3.4.21.37) is 218 amino acids long, with two asparagine-linked carbohydrate chains (see glycosylation). It is present in azurophil granules in the neutrophil cytoplasm. There appear to be two forms of neutrophil elastase, termed IIa and IIb.

Gene

In humans, neutrophil elastase is encoded by the ELANE gene, which resides on chromosome 19.[7]

Function

Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes that encode the structurally similar proteins elastase 1, 2, 2A, 2B, 3A, and 3B. Neutrophil elastase hydrolyzes proteins within specialized neutrophil lysosomes, called azurophil granules, as well as proteins of the extracellular matrix following the protein's release from activated neutrophils. Neutrophil elastase may play a role in degenerative and inflammatory diseases by its proteolysis of collagen-IV and elastin of the extracellular matrix. This protein degrades the outer membrane protein A (OmpA) of E. coli as well as the virulence factors of such bacteria as Shigella, Salmonella and Yersinia.[8] Mutations in this gene are associated with cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). This gene is clustered with other serine protease gene family members, azurocidin 1 and proteinase 3 genes, at chromosome 19pter. All 3 genes are expressed coordinately and their protein products are packaged together into azurophil granules during neutrophil differentiation.[9]

Clinical significance

Neutrophil elastase is an important protease enzyme that when expressed aberrantly can cause emphysema or emphysematous changes. This involves breakdown of the lung structure and increased airspaces. Mutations of the ELANE gene cause cyclic and severe congenital neutropenia, which is a failure of neutrophils to mature.[10] In 2019 study was confirmed that ELANE deletion does not cause neutropenia.[11]

Inhibitors

In order to minimize damage to tissues, there are few inhibitors of neutrophil elastase. One group of inhibitors are the Serpins (Serine Protease Inhibitors).[12] Neutrophil elastase has been shown to interact with Alpha 2-antiplasmin, which belongs to the Serpin family of proteins.[13][14]

See also

• Elastase

References

1. ENSG00000197561 GRCh38: Ensembl release 89: ENSG00000277571, ENSG00000197561 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020125 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Belaaouaj A, Kim KS, Shapiro SD (August 2000). "Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase". Science. 289 (5482): 1185–8. doi:10.1126/science.289.5482.1185. PMID 10947984.
6. Thomas MP, Whangbo J, McCrossan G, Deutsch AJ, Martinod K, Walch M, Lieberman J (June 2014). "Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins". J. Immunol. 192 (11): 5390–7. doi:10.4049/jimmunol.1303296. PMC 4041364. PMID 24771851.
7. Takahashi H, Nukiwa T, Yoshimura K, Quick CD, States DJ, Holmes MD, Whang-Peng J, Knutsen T, Crystal RG (October 1988). "Structure of the human neutrophil elastase gene". J. Biol. Chem. 263 (29): 14739–47. PMID 2902087.
8. Weinrauch Y, Drujan D, Shapiro SD, Weiss J, Zychlinsky A (May 2002). "Neutrophil elastase targets virulence factors of enterobacteria". Nature. 417 (6884): 91–4. doi:10.1038/417091a. PMID 12018205.
9. "Entrez Gene: ELA2 elastase 2, neutrophil".
10. Dale DC, Link DC (January 2009). "The many causes of severe congenital neutropenia". N. Engl. J. Med. 360 (1): 3–5. doi:10.1056/NEJMp0806821. PMC 4162527. PMID 19118300.
11. Horwitz MS, Laurino MY, Keel SB (August 2019). "ELANE whole gene deletion mutation". Blood Advances. 3 (16): 2470–2473. doi:10.1182/bloodadvances.2019000498. PMC 6712528. PMID 31427279.
12. Korkmaz B, Horwitz MS, Jenne DE, Gauthier F (December 2010). "Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases". Pharmacol. Rev. 4 (62): 726–59. doi:10.1124/pr.110.002733. PMC 2993259. PMID 21079042.
13. Brower MS, Harpel PC (August 1982). "Proteolytic cleavage and inactivation of alpha 2-plasmin inhibitor and C1 inactivator by human polymorphonuclear leukocyte elastase". J. Biol. Chem. 257 (16): 9849–54. PMID 6980881.
14. Shieh BH, Travis J (May 1987). "The reactive site of human alpha 2-antiplasmin". J. Biol. Chem. 262 (13): 6055–9. PMID 2437112.

Further reading

• Dale DC, Liles WC, Garwicz D, Aprikyan AG (2001). "Clinical implications of mutations of neutrophil elastase in congenital and cyclic neutropenia". J. Pediatr. Hematol. Oncol. 23 (4): 208–10. doi:10.1097/00043426-200105000-00005. PMID 11846296.
• Horwitz M, Benson KF, Duan Z, Person RE, Wechsler J, Williams K, Albani D, Li FQ (2003). "Role of neutrophil elastase in bone marrow failure syndromes: molecular genetic revival of the chalone hypothesis". Curr. Opin. Hematol. 10 (1): 49–54. doi:10.1097/00062752-200301000-00008. PMID 12483111.
• Ancliff PJ, Gale RE, Linch DC (2003). "Neutrophil elastase mutations in congenital neutropenia". Hematology. 8 (3): 165–71. doi:10.1080/1024533031000107497. PMID 12745650.
• Horwitz M, Benson KF, Duan Z, Li FQ, Person RE (2004). "Hereditary neutropenia: dogs explain human neutrophil elastase mutations". Trends Mol Med. 10 (4): 163–70. doi:10.1016/j.molmed.2004.02.002. PMID 15059607.

External links

• GeneReviews/NCBI/NIH/UW entry on ELANE-Related Neutropenias
• Neutrophil+Elastase at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P08246 (Neutrophil elastase) at the PDBe-KB.