AOAH
Identifiers
AliasesAOAH, acyloxyacyl hydrolase
External IDsOMIM: 102593 MGI: 1350928 HomoloGene: 1238 GeneCards: AOAH
Orthologs
SpeciesHumanMouse
Entrez

313

27052

Ensembl

ENSG00000136250

ENSMUSG00000021322

UniProt

P28039

O35298

RefSeq (mRNA)

NM_001177506
NM_001177507
NM_001637

NM_001281854
NM_012054

RefSeq (protein)

NP_001170977
NP_001170978
NP_001628

NP_001268783
NP_036184

Location (UCSC)Chr 7: 36.51 – 36.72 MbChr 13: 20.98 – 21.22 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Acyloxyacyl hydrolase, also known as AOAH, is a eukaryotic protein encoded by the AOAH gene.[5] AOAH is produced by macrophages (including Kupffer cells and microglia), dendritic cells (especially in the colon), NK cells, ILC1 cells, neutrophils and renal proximal tubule cells.[6]

Species distribution

The AOAH gene has been found in many invertebrates and in all vertebrates studied to date except fish. Although mice have other well-established mechanisms for preventing LPS signaling, none of these has prevented long-term persistence of stimulatory LPS in animals that lack AOAH.[7][8]

Structure

The enzyme's 2 disulfide-linked subunits are encoded by a single mRNA. The smaller subunit is a member of the saposin-like (SAPLIP) protein family and the larger subunit, which contains the active site serine, is a GDSL lipase. The enzyme's 3D structure and catalytic mechanism were reported by Gorelik et al.[9]

Function

Acyloxyacyl hydrolase (AOAH) is a lipase that selectively releases the secondary (acyloxyacyl-linked) fatty acyl chains from the hexaacyl lipid A moiety found in many bacterial lipopolysaccharides (LPSs, also called endotoxins).[5][6] The resulting tetraacyl LPS is non-stimulatory and can be a potent inhibitor of LPS sensing via the MD-2--Toll-like Receptor 4 (TLR4). The enzyme's other known substrates include bacterial lipopeptides and several host glycerolipids, including lyso-and oxidized phospholipids.[6][10]

Animal studies

Absence of the enzyme in genetically engineered mice has been associated with distinctive phenotypes. AOAH-deficient animals are unable to inactivate even small amounts of LPS in most tissues; the LPS remains bioactive and may pass from cell to cell in vivo for many weeks. The LPS-injected mice develop strikingly high titers of polyclonal antibodies, prolonged hepatomegaly, and innate immune "tolerance" that results in slow and inadequate responses to a bacterial challenge. Absence of the enzyme renders mice more likely to develop severe lung injury and die if they are challenged with intratracheal LPS, Gram-negative bacteria, or acid (AOAH may also inactivate oxidized phospholipids).[10][11] Other studies have found that AOAH reduces the stimulatory potency of LPS that translocates from the gastrointestinal tract to the liver and other organs.[12] AOAH may also prevent LPS-induced arterial foam cell formation in vivo.[13]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000136250 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021322 - 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. 1 2 Hall CL, Munford RS (November 1983). "Enzymatic deacylation of the lipid A moiety of Salmonella typhimurium lipopolysaccharides by human neutrophils". Proceedings of the National Academy of Sciences of the United States of America. 80 (21): 6671–6675. Bibcode:1983PNAS...80.6671H. doi:10.1073/pnas.80.21.6671. PMC 391232. PMID 6356132.
  6. 1 2 3 Munford RS, Weiss JP, Lu M (December 2020). "Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery". The Journal of Biological Chemistry. 295 (51): 17842–17851. doi:10.1074/jbc.REV120.015254. PMC 7762960. PMID 33454018.
  7. ↑ 8Lu M, Varley AW, Ohta S, Hardwick J, Munford RS (September 2008). "Host inactivation of bacterial lipopolysaccharide prevents prolonged tolerance following gram-negative bacterial infection". Cell Host & Microbe. 4 (3): 293–302. doi:10.1016/j.chom.2008.06.009. PMC 2607035. PMID 18779055.
  8. ↑ Lu M, Varley AW, Munford RS (May 2013). "Persistently active microbial molecules prolong innate immune tolerance in vivo". PLOS Pathogens. 9 (5): e1003339. doi:10.1371/journal.ppat.1003339. PMC 3649966. PMID 23675296.
  9. ↑ Gorelik A, Illes K, Nagar B (January 2018). "Crystal structure of the mammalian lipopolysaccharide detoxifier". Proceedings of the National Academy of Sciences of the United States of America. 115 (5): E896–E905. Bibcode:2018PNAS..115E.896G. doi:10.1073/pnas.1719834115. PMC 5798384. PMID 29343645.
  10. 1 2 Zou B, Goodwin M, Saleem D, Jiang W, Tang J, Chu Y, et al. (November 2021). "A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury in mice". eLife. 10 (10). doi:10.7554/eLife.70938. PMC 594946. PMID 34783310.
  11. ↑ Zou B, Jiang W, Han H, Li J, Mao W, Tang Z, et al. (June 2017). "Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury". PLOS Pathogens. 13 (6): e1006436. doi:10.1371/journal.ppat.1006436. PMC 5489216. PMID 28622363.
  12. ↑ Qian G, Jiang W, Zou B, Feng J, Cheng X, Gu J, et al. (September 2018). "LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma". The Journal of Experimental Medicine. 215 (9): 2397–2412. doi:10.1084/jem.20172225. PMC 6122967. PMID 30021797.
  13. ↑ Feng J, Jiang W, Cheng X, Zou B, Varley AW, Liu T, et al. (September 2021). "A host lipase prevents lipopolysaccharide-induced foam cell formation". iScience. 24 (9): 103004. Bibcode:2021iSci...24j3004F. doi:10.1016/j.isci.2021.103004. PMC 8426562. PMID 34522852.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.