Deacylation and palmitoylation of lipid A by Salmonellae outer membrane enzymes modulate host signaling through Toll-like receptor 4.
The Salmonella typhimurium virulence gene products, PhoP/PhoQ sense host micro-environments to regulate the expression of a lipid A 3-O-deacylase, PagL, and a lipid A palmitoyltransferase, PagP. Therefore, deacylation and/or palmitoylation of lipid A could occur in Salmonellae adapted to host environments. The acylation state of lipid A can alter host recognition and signaling by Toll-like receptor (TLR) 4, and may play an important role in host defenses against Salmonellae infection. Deacylated lipid A, deacylated and palmitoylated lipid A, palmitoylated lipid A, and unmodified lipid A species were purified, and the activity was examined using cell lines expressing recombinant human or mouse TLR4. Compared with unmodified lipid A, the modified lipid A species are 10-100-fold less active. These results suggest that PagL and PagP modify lipid A to reduce TLR4-signaling as part of Salmonellae adaptation to the host environment.
Kawasaki
Kiyoshi
K
Department of Microbiology, University of Washington, Seattle, Washington 98195, USA.
Ernst
Robert K
RK
Miller
Samuel I
SI
D000217:Acyltransferases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008050:Lipid A / Q000737:chemistry / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000201:enzymology*; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D008050:Lipid A; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000217:Acyltransferases; C468520:PagP protein, E coli; D002265:Carboxylic Ester Hydrolases; C424702:PagL protein, Salmonella typhimurium