AOAH: Difference between revisions

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== Function ==
== Function ==


Acyloxyacyl hydrolase (AOAH) is a 2-subunit [[lipase]] which selectively hydrolyzes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial [[lipopolysaccharide]]s (LPSs, also called endotoxins).  This action inactivates LPSs that are sensed by MD-2--Toll-like Receptor 4 ([[TLR 4]]) on animal cells (and probably also by the cytosolic caspase-based sensors).  The enzyme's 2 disulfide-linked subunits are encoded by a single mRNA.  The smaller subunit is a member of the saposin-like (SAPLIP) proteins and the larger subunit, which contains the active site serine,is a GDSL lipase.
Acyloxyacyl hydrolase (AOAH) is a 2-subunit [[lipase]] which selectively hydrolyzes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial [[lipopolysaccharide]]s (LPSs, also called endotoxins).  This action inactivates LPSs that are sensed by MD-2--Toll-like Receptor 4 ([[TLR 4]]) on animal cells (and probably also by the cytosolic caspase-based sensors).  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.


AOAH is produced by neutrophils, macrophages (including Kupffer cells and microglia), dendritic cells, NK cells and renal proximal tubule cells.  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 tissues; it remains bioactive and may pass from cell to cell in vivo for many weeks.  The LPS-exposed mice develop strikingly high titers of polyclonal antibodies, prolonged hepatomegaly, and innate immune "tolerance" that gives them slow and inadequate responses to bacterial challenge.
AOAH is produced by neutrophils, macrophages (including Kupffer cells and microglia), dendritic cells, NK cells and renal proximal tubule cells.  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; it remains bioactive and may pass from cell to cell in vivo for many weeks.  The LPS-exposed mice develop strikingly high titers of polyclonal antibodies, prolonged hepatomegaly, and innate immune "tolerance" that gives them slow and inadequate responses to bacterial challenge. In contrast, absence of the enzyme renders mice more likely to develop severe lung injury and die if they are challenged with intratracheal LPS or Gram-negative bacteria. 


AOAH has been highly conserved through evolution; the amino acid sequence of the human enzyme is  almost 50% identical to that of the AOAH found in Dictyostelium discoideum, with 100% identity in the GDSL lipase consensus sequences.  The enzyme has been found in many invertebrates and all vertebrates studied to date except fish.  Although it seems likely that the enzyme has substrates in vivo other than LPS (it can be a phospholipase A1/B and acyl transferase in vitro), none has been identified.
AOAH has been highly conserved through evolution; the amino acid sequence of the human enzyme is  almost 50% identical to that of the AOAH found in Dictyostelium discoideum, with 100% identity in the GDSL lipase consensus sequences.  The enzyme has been found in many invertebrates and all vertebrates studied to date except fish.  Although it seems likely that the enzyme has substrates in vivo other than LPS (it can be a phospholipase A1/B and acyl transferase in vitro), none has been identified.
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*{{cite journal |vauthors=Fairfax BP, Makino S, Radhakrishnan J, Knight JC |title=Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles |journal=Nat. Genet.|volume = 44|pages = 502–510|year=2012|pmid=22446964|doi=10.1038/ng.2205|display-authors=etal |pmc=3437404}}
*{{cite journal |vauthors=Fairfax BP, Makino S, Radhakrishnan J, Knight JC |title=Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles |journal=Nat. Genet.|volume = 44|pages = 502–510|year=2012|pmid=22446964|doi=10.1038/ng.2205|display-authors=etal |pmc=3437404}}
*{{cite journal |author =Lu M|author2 =Varley AW|author3 =Ohta S|author4 =Hardwick J|author5=Munford RS |title=Host inactivation of bacterial lipopolysaccharide prevents prolonged tolerance following gram-negative bacterial infection |journal=Cell Host Microbe| volume=4|pages=293–302|year=2008|pmid=18779055 |doi=10.1016/j.chom.2008.06.009 |pmc=2607035}}
*{{cite journal |author =Lu M|author2 =Varley AW|author3 =Ohta S|author4 =Hardwick J|author5=Munford RS |title=Host inactivation of bacterial lipopolysaccharide prevents prolonged tolerance following gram-negative bacterial infection |journal=Cell Host Microbe| volume=4|pages=293–302|year=2008|pmid=18779055 |doi=10.1016/j.chom.2008.06.009 |pmc=2607035}}
*{{cite journal |vauthors=Lu M, Varley AW, Munford RS |title=Persistently active microbial molecules prolong innate immune tolerance in vivo |journal=PLOS Pathogens|volume=9|page= e1003339 |year=2013|pmid= 23675296 |doi=10.1371/journal.ppat.1003339 |pmc=3649966}}
*{{cite journal |vauthors=Lu M, Varley AW, Munford RS |title=Persistently active microbial molecules prolong innate immune tolerance in vivo |journal=PLOS Pathogens|volume=9|page= e1003339 |year=2013|pmid=23675296 |doi= 10.1371/journal.ppat.1003339 |pmc= 3649966}}
}}
*{{cite journal |vauthors= Zou B, Jiang W, Han H,Lu M |title= Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury |journal=PLOS Pathogens |volume= 13 |page= e1006436 |year=2017 |pmid= 28622363 |doi= 10.1371/journal.ppat.1006436 |pmc= 5489216}}
*{{cite journal |vauthors=Gorelik A, Illes K, Nagar B |title= Crystal structure of the mammalian lipopolysaccharide detoxifier |journal= PNAS |volume= 115 |page= E896-E905 |year=2018 |pmid= 29343645 |doi= 10.1073/journal.pnas.1719834115 |pmc= 5798384}}
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Latest revision as of 04:18, 3 April 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Acyloxyacyl hydrolase, also known as AOAH, is a protein which in humans is encoded by the AOAH gene.

Function

Acyloxyacyl hydrolase (AOAH) is a 2-subunit lipase which selectively hydrolyzes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides (LPSs, also called endotoxins). This action inactivates LPSs that are sensed by MD-2--Toll-like Receptor 4 (TLR 4) on animal cells (and probably also by the cytosolic caspase-based sensors). 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.

AOAH is produced by neutrophils, macrophages (including Kupffer cells and microglia), dendritic cells, NK cells and renal proximal tubule cells. 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; it remains bioactive and may pass from cell to cell in vivo for many weeks. The LPS-exposed mice develop strikingly high titers of polyclonal antibodies, prolonged hepatomegaly, and innate immune "tolerance" that gives them slow and inadequate responses to bacterial challenge. In contrast, absence of the enzyme renders mice more likely to develop severe lung injury and die if they are challenged with intratracheal LPS or Gram-negative bacteria.

AOAH has been highly conserved through evolution; the amino acid sequence of the human enzyme is almost 50% identical to that of the AOAH found in Dictyostelium discoideum, with 100% identity in the GDSL lipase consensus sequences. The enzyme has been found in many invertebrates and all vertebrates studied to date except fish. Although it seems likely that the enzyme has substrates in vivo other than LPS (it can be a phospholipase A1/B and acyl transferase in vitro), none has been identified.

A polymorphism in the gene has been associated with chronic rhinosinusitis in 2 different ethnic groups. Other studies have found that AOAH mRNA abundance is linked to HLA-DR alleles that, in turn, have been associated strongly with colitis.

References

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External links


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