SLPI

SLPI
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSLPI, ALK1, ALP, BLPI, HUSI, HUSI-I, MPI, WAP4, WFDC4, secretory leukocyte peptidase inhibitor
External IDsMGI: 109297 HomoloGene: 2305 GeneCards: SLPI
Gene location (Human)
Chr.Chromosome 20 (human)[1]
Band20q13.12Start45,252,239 bp[1]
End45,254,564 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

6590

20568

Ensembl

ENSG00000124107

ENSMUSG00000017002

UniProt

P03973

P97430

RefSeq (mRNA)

NM_003064

NM_011414

RefSeq (protein)

NP_003055

NP_035544

Location (UCSC)Chr 20: 45.25 – 45.25 MbChr 2: 164.35 – 164.39 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the SLPI gene.[5][6][7] SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in large quantities in bronchial, cervical, and nasal mucosa, saliva, and seminal fluids. SLPI inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. X-ray crystallography has shown that SLPI has two homologous domains of 53 and 54 amino acids, one of which exhibits anti-protease activity (C-terminal domain). The other domain (N-terminal domain) is not known to have any function.

Function

This gene encodes a secreted inhibitor which protects epithelial tissues from serine proteases. It is found in various secretions including seminal plasma, cervical mucus, and bronchial secretions, and has affinity for trypsin, leukocyte elastase, and cathepsin G. Its inhibitory effect contributes to the immune response by protecting epithelial surfaces from attack by endogenous proteolytic enzymes; the protein is also thought to have broad-spectrum anti-biotic activity.[7]

Clinical significance

The gene for SLPI is expressed by cells at many mucosal surfaces located in the tissues of the lungs, cervix, seminal vesicles, and parotid ducts. SLPI is also one of the dominantly present proteins in nasal epithelial lining fluid and other nasal secretions. Tissue SLPI expression reveals a clear compartmentalization, being highest in the endocervix and lowest in the endometrium of postmenopausal women. Hormonal treatment differentially modulates tissue SLPI expression along the reproductive tract [8]. Many diseases, such as emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis, are characterized by increased levels of neutrophil elastase. SLPI is one of the major defenses against the destruction of pulmonary tissues and epithelial tissues by neutrophil elastase. SLPI is considered to be the predominant elastase inhibitor in secretions, while α1-antitrypsin is the predominant elastase inhibitor in tissues. Several diseases, including those listed, are actually the result of SLPI and α1-antitrypsin defenses being overwhelmed by neutrophil elastase. It has been suggested that recombinant human SLPI be administered to treat symptoms of cystic fibrosis, genetic emphysema, and asthma. In addition, SLPI has occasionally been monitored in an effort to coordinate its levels with different pathological conditions. Increased levels of SLPI in nasal secretions and bronchoalveolar fluids may be denotive of inflammatory lung conditions or allergic reactions, and increased levels of SLPI in plasma may be indicative of pneumonia.[9]

Increased levels of SLPI in saliva and plasma may also be an indicator of HIV infection. This is evident due to the virtual nonexistence of HIV transmission through oral-to-oral contact. This antiviral activity is due to the interference of SLPI in events that are mediated by protease, such as entry into the host cell and replication of viral genetic material. Studies have shown that decreasing levels of SLPI in saliva also decreases its anti-HIV activity.[9][10][11][12] What makes SLPI such a topic of interest is that it exhibits anti-HIV properties in physiological conditions, rather than artificial ones.[9]

Furthermore, it has been shown that there is an inverse correlation between the levels of SLPI and high-risk Human Papillomavirus (HPV) infection, demonstrating that high levels of SLPI confer protection against HPV infection.[13][14][15]

Interactions

SLPI has been shown to interact with PLSCR1 and PLSCR4 on the plasma membrane of T-cells, specifically in the proximity of CD4.[16][17] This interaction is hypothesized to be one of the ways SLPI inhibits HIV infection.

Additionally, it has been shown that SLPI is able to bind the Annexin A2/S100A10 heterotetramer (A2t), a co-factor HIV infection, on the surface of macrophages.[18] This interaction with A2t has also been shown to block HPV uptake and infection of epithelial cells.[19]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000124107 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000017002 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Stetler G, Brewer MT, Thompson RC (Oct 1986). "Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases". Nucleic Acids Research. 14 (20): 7883–96. doi:10.1093/nar/14.20.7883. PMC 311822. PMID 3640338.
  6. ↑ Clauss A, Lilja H, Lundwall A (Nov 2002). "A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein". The Biochemical Journal. 368 (Pt 1): 233–42. doi:10.1042/BJ20020869. PMC 1222987. PMID 12206714.
  7. 1 2 "Entrez Gene: SLPI secretory leukocyte peptidase inhibitor".
  8. ↑ Kumar R, Vicari M, Gori I, Achtari C, Fiche M, Surbeck I, Damnon F, Canny GO (September 2011). "Compartmentalized secretory leukocyte protease inhibitor expression and hormone responses along the reproductive tract of postmenopausal women". J Reprod Immunol. 92 (1–2): 88–96. doi:10.1016/j.jri.2011.06.103. PMID 21940052.
  9. 1 2 3 McNeely TB, Dealy M, Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM (Jul 1995). "Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro". The Journal of Clinical Investigation. 96 (1): 456–64. doi:10.1172/JCI118056. PMC 185219. PMID 7615818.
  10. ↑ Nagashunmugam T, Malamud D, Davis C, Abrams WR, Friedman HM (Dec 1998). "Human submandibular saliva inhibits human immunodeficiency virus type 1 infection by displacing envelope glycoprotein gp120 from the virus". The Journal of Infectious Diseases. 178 (6): 1635–41. doi:10.1086/314511. PMID 9815215.
  11. ↑ Shugars DC, Wahl SM (Jul 1998). "The role of the oral environment in HIV-1 transmission". Journal of the American Dental Association. 129 (7): 851–8. doi:10.14219/jada.archive.1998.0349. PMID 9685760.
  12. ↑ Malamud D, Friedman HM (1993-01-01). "HIV in the oral cavity: virus, viral inhibitory activity, and antiviral antibodies: a review". Critical Reviews in Oral Biology and Medicine. 4 (3–4): 461–6. PMID 8373998.
  13. ↑ Hoffmann M, Quabius ES, Tribius S, Hebebrand L, Görögh T, Halec G, Kahn T, Hedderich J, Röcken C, Haag J, Waterboer T, Schmitt M, Giuliano AR, Kast WM (May 2013). "Human papillomavirus infection in head and neck cancer: the role of the secretory leukocyte protease inhibitor". Oncology Reports. 29 (5): 1962–8. doi:10.3892/or.2013.2327. PMC 3658815. PMID 23467841.
  14. ↑ Pierce Campbell CM, Guan W, Sprung R, Koomen JM, O'Keefe MT, Ingles DJ, Abrahamsen M, Giuliano AR (Dec 2013). "Quantification of secretory leukocyte protease inhibitor (SLPI) in oral gargle specimens collected using mouthwash". Journal of Immunological Methods. 400-401: 117–21. doi:10.1016/j.jim.2013.10.005. PMC 3990009. PMID 24140751.
  15. ↑ Quabius ES, Möller P, Haag J, Pfannenschmidt S, Hedderich J, Görögh T, Röcken C, Hoffmann M (Mar 2014). "The role of the antileukoprotease SLPI in smoking-induced human papillomavirus-independent head and neck squamous cell carcinomas". International Journal of Cancer. 134 (6): 1323–34. doi:10.1002/ijc.28462. PMID 23996702.
  16. ↑ Tseng CC, Tseng CP (Jun 2000). "Identification of a novel secretory leukocyte protease inhibitor-binding protein involved in membrane phospholipid movement". FEBS Letters. 475 (3): 232–6. doi:10.1016/s0014-5793(00)01700-2. PMID 10869562.
  17. ↑ Py B, Basmaciogullari S, Bouchet J, Zarka M, Moura IC, Benhamou M, Monteiro RC, Hocini H, Madrid R, Benichou S (2009-01-01). "The phospholipid scramblases 1 and 4 are cellular receptors for the secretory leukocyte protease inhibitor and interact with CD4 at the plasma membrane". PLOS ONE. 4 (3): e5006. doi:10.1371/journal.pone.0005006. PMC 2659420. PMID 19333378.
  18. ↑ Ma G, Greenwell-Wild T, Lei K, Jin W, Swisher J, Hardegen N, Wild CT, Wahl SM (Nov 2004). "Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection". The Journal of Experimental Medicine. 200 (10): 1337–46. doi:10.1084/jem.20041115. PMC 2211913. PMID 15545357.
  19. ↑ Woodham AW, Da Silva DM, Skeate JG, Raff AB, Ambroso MR, Brand HE, Isas JM, Langen R, Kast WM (2012-01-01). "The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection". PLOS ONE. 7 (8): e43519. doi:10.1371/journal.pone.0043519. PMC 3425544. PMID 22927980.

Further reading

  • Reviglio VE, Sambuelli RH, Olmedo A, Falco M, Echenique J, O'Brien TP, Kuo IC (2007). "Secretory leukocyte protease inhibitor is an inducible antimicrobial peptide expressed in Staphylococcus aureus endophthalmitis". Mediators of Inflammation. 2007: 93857. doi:10.1155/2007/93857. PMC 2234354. PMID 18274645.
  • Fritz H (May 1988). "Human mucus proteinase inhibitor (human MPI). Human seminal inhibitor I (HUSI-I), antileukoprotease (ALP), secretory leukocyte protease inhibitor (SLPI)". Biological Chemistry Hoppe-Seyler. 369 Suppl: 79–82. PMID 3060147.
  • Sallenave JM (2003). "The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor/skin-derived antileukoprotease) as alarm antiproteinases in inflammatory lung disease". Respiratory Research. 1 (2): 87–92. doi:10.1186/rr18. PMC 59548. PMID 11667971.
  • Rogaev EI, Keryanov SA, Malyako YK (Jul 1992). "Dinucleotide repeat polymorphisms at the P1, HBE1 and MYH7 loci". Human Molecular Genetics. 1 (4): 285. doi:10.1093/hmg/1.4.285. PMID 1363870.
  • Abe T, Kobayashi N, Yoshimura K, Trapnell BC, Kim H, Hubbard RC, Brewer MT, Thompson RC, Crystal RG (Jun 1991). "Expression of the secretory leukoprotease inhibitor gene in epithelial cells". The Journal of Clinical Investigation. 87 (6): 2207–15. doi:10.1172/JCI115255. PMC 296981. PMID 1674946.
  • Sallenave JM, Ryle AP (Jan 1991). "Purification and characterization of elastase-specific inhibitor. Sequence homology with mucus proteinase inhibitor". Biological Chemistry Hoppe-Seyler. 372 (1): 13–21. doi:10.1515/bchm3.1991.372.1.13. PMID 2039600.
  • Eisenberg SP, Hale KK, Heimdal P, Thompson RC (May 1990). "Location of the protease-inhibitory region of secretory leukocyte protease inhibitor". The Journal of Biological Chemistry. 265 (14): 7976–81. PMID 2110563.
  • Grütter MG, Fendrich G, Huber R, Bode W (Feb 1988). "The 2.5 A X-ray crystal structure of the acid-stable proteinase inhibitor from human mucous secretions analysed in its complex with bovine alpha-chymotrypsin". The EMBO Journal. 7 (2): 345–51. PMC 454325. PMID 3366116.
  • Thompson RC, Ohlsson K (Sep 1986). "Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase". Proceedings of the National Academy of Sciences of the United States of America. 83 (18): 6692–6. doi:10.1073/pnas.83.18.6692. PMC 386575. PMID 3462719.
  • Seemüller U, Arnhold M, Fritz H, Wiedenmann K, Machleidt W, Heinzel R, Appelhans H, Gassen HG, Lottspeich F (Apr 1986). "The acid-stable proteinase inhibitor of human mucous secretions (HUSI-I, antileukoprotease). Complete amino acid sequence as revealed by protein and cDNA sequencing and structural homology to whey proteins and Red Sea turtle proteinase inhibitor". FEBS Letters. 199 (1): 43–8. doi:10.1016/0014-5793(86)81220-0. PMID 3485543.
  • Heinzel R, Appelhans H, Gassen G, Seemüller U, Machleidt W, Fritz H, Steffens G (Oct 1986). "Molecular cloning and expression of cDNA for human antileukoprotease from cervix uterus". European Journal of Biochemistry / FEBS. 160 (1): 61–7. doi:10.1111/j.1432-1033.1986.tb09940.x. PMID 3533531.
  • Westin U, Fryksmark U, Polling A, Ohlsson K (Mar 1994). "Localisation of secretory leucocyte proteinase inhibitor mRNA in nasal mucosa". Acta Oto-Laryngologica. 114 (2): 199–202. doi:10.3109/00016489409126042. PMID 7515550.
  • Ohlsson K, Bjartell A, Lilja H (1995). "Secretory leucocyte protease inhibitor in the male genital tract: PSA-induced proteolytic processing in human semen and tissue localization". Journal of Andrology. 16 (1): 64–74. PMID 7539415.
  • Belorgey D, Dirrig S, Amouric M, Figarella C, Bieth JG (Jan 1996). "Inhibition of human pancreatic proteinases by mucus proteinase inhibitor, eglin c and aprotinin". The Biochemical Journal. 313 ( Pt 2) (2): 555–60. PMC 1216943. PMID 8573092.
  • Kikuchi T, Abe T, Hoshi S, Matsubara N, Tominaga Y, Satoh K, Nukiwa T (Dec 1998). "Structure of the murine secretory leukoprotease inhibitor (Slpi) gene and chromosomal localization of the human and murine SLPI genes". American Journal of Respiratory Cell and Molecular Biology. 19 (6): 875–80. doi:10.1165/ajrcmb.19.6.3314. PMID 9843921.
  • Westin U, Polling A, Ljungkrantz I, Ohlsson K (Apr 1999). "Identification of SLPI (secretory leukocyte protease inhibitor) in human mast cells using immunohistochemistry and in situ hybridisation". Biological Chemistry. 380 (4): 489–93. doi:10.1515/BC.1999.063. PMID 10355635.
  • Mulligan MS, Lentsch AB, Huber-Lang M, Guo RF, Sarma V, Wright CD, Ulich TR, Ward PA (Mar 2000). "Anti-inflammatory effects of mutant forms of secretory leukocyte protease inhibitor". The American Journal of Pathology. 156 (3): 1033–9. doi:10.1016/S0002-9440(10)64971-1. PMC 1876846. PMID 10702419.
  • Nyström M, Bergenfeldt M, Ljungcrantz I, Lindeheim A, Ohlsson K (2000). "Production of secretory leucocyte protease inhibitor (SLPI) in human pancreatic beta-cells". Mediators of Inflammation. 8 (3): 147–51. doi:10.1080/09629359990478. PMC 1781797. PMID 10704052.
  • Si-Tahar M, Merlin D, Sitaraman S, Madara JL (Jun 2000). "Constitutive and regulated secretion of secretory leukocyte proteinase inhibitor by human intestinal epithelial cells". Gastroenterology. 118 (6): 1061–71. doi:10.1016/S0016-5085(00)70359-3. PMID 10833481.
  • Victor E. Reviglio, Andres Grenat, Federico Pegoraro, Ruben H. Sambuelli, Tayyib Rana, and Irene C. Kuo. Secretory Leukoprotease Inhibitor: A Native Antimicrobial Protein in the Innate Immune Response in a Rat Model of S. aureus Keratitis. Journal of OphthalmologyVolume 2009 (2009), Article ID 259393, 5 pages doi:10.1155/2009/259393
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