| Reference | 1. Nature. 2014 Aug 28;512(7515):387-92. doi: 10.1038/nature13684. Epub 2014 Aug 13. <br />
AhR sensing of bacterial pigments regulates antibacterial defence. <br />
Moura-Alves P(1), Faé K(1), Houthuys E(1), Dorhoi A(1), Kreuchwig A(2), Furkert
J(2), Barison N(3), Diehl A(2), Munder A(4), Constant P(5), Skrahina T(6),
Guhlich-Bornhof U(6), Klemm M(6), Koehler AB(6), Bandermann S(6), Goosmann C(7),
Mollenkopf HJ(8), Hurwitz R(9), Brinkmann V(7), Fillatreau S(10), Daffe M(5),
Tümmler B(4), Kolbe M(3), Oschkinat H(2), Krause G(2), Kaufmann SH(6). <br />
Author information: <br />
(1)1] Max Planck Institute for Infection Biology, Department of Immunology,
Charitéplatz 1, 10117 Berlin, Germany [2].
(2)Leibniz Institute for Molecular Pharmacology (FMP), Robert-Rössle-Strasse 10,
13125 Berlin, Germany.
(3)Max Planck Institute for Infection Biology, Structural Systems Biology,
Charitéplatz 1, 10117 Berlin, Germany.
(4)Clinical Research Group, Clinic for Pediatric Pneumology, Allergology and
Neonatology, OE 6710, Hannover Medical School, Carl-Neuberg-Str. 1, 30625
Hannover, Germany.
(5)Institute of Pharmacology and Structural Biology (IPBS), CNRS and University
of Toulouse (Toulouse III), 205 Route de Narbonne, 31077, Toulouse cedex 04,
Toulouse, France.
(6)Max Planck Institute for Infection Biology, Department of Immunology,
Charitéplatz 1, 10117 Berlin, Germany.
(7)Microscopy Core Facility, Max Planck Institute for Infection Biology,
Department of Immunology, Charitéplatz 1, 10117 Berlin, Germany.
(8)Microarray Core Facility, Max Planck Institute for Infection Biology,
Department of Immunology, Charitéplatz 1, 10117 Berlin, Germany.
(9)Protein Purification Core Facility, Max Planck Institute for Infection
Biology, Charitéplatz 1, 10117 Berlin, Germany.
(10)German Rheumatism Research Centre Berlin (DRFZ), a Leibniz Institute,
Charitéplatz 1, 10117 Berlin, Germany. <br />
The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent
transcription factor that senses environmental toxins and endogenous ligands,
thereby inducing detoxifying enzymes and modulating immune cell differentiation
and responses. We hypothesized that AhR evolved to sense not only environmental
pollutants but also microbial insults. We characterized bacterial pigmented
virulence factors, namely the phenazines from Pseudomonas aeruginosa and the
naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon
ligand binding, AhR activation leads to virulence factor degradation and
regulated cytokine and chemokine production. The relevance of AhR to host defence
is underlined by heightened susceptibility of AhR-deficient mice to both P.
aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct
bacterial virulence factors and controls antibacterial responses, supporting a
previously unidentified role for AhR as an intracellular pattern recognition
receptor, and identify bacterial pigments as a new class of pathogen-associated
molecular patterns. <br />
2. Chem Biol. 1995 Dec;2(12):841-5. <br />
Structure elucidation of two tryptophan-derived, high affinity Ah receptor
ligands. <br />
Rannug U(1), Rannug A, Sjöberg U, Li H, Westerholm R, Bergman J. <br />
Author information: <br />
(1)Department of Genetic and Cellular Toxicology, Wallenberg Laboratory,
Stockholm University, Sweden. <br />
BACKGROUND: Environmental contaminants, such as
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other structurally related
/’environmental hormones/’, exert their harmful biological effects through the Ah
receptor signaling pathway. Several naturally occurring substances also bind to
this receptor, but its natural role is still obscure. Tryptophan derivatives of
the indolo[3,2-b]carbazole type, earlier suggested by us to be endogenous ligands
for the receptor, should be a powerful tool in understanding receptor function.
We therefore set out to determine their identity.<br />
RESULTS: The two tryptophan-derived Ah receptor ligands have been chemically
analyzed and characterized by means of mass spectrometry, 1H NMR and 13C NMR. UV,
infra-red and fluorescence spectra were also recorded. All data are in accordance
with the two compounds being closely related indolo[3,2-b]carbazole derivatives.
Evidence is presented that compound A (MW = 312) is the symmetrical
6,12-diformylindolo[3,2-b]carbazole, and compound B (MW = 284) is the
monosubstituted 6-formylindolo[3,2-b]carbazole.<br />
CONCLUSIONS: The elucidation of the structures of the two high affinity Ah
receptor ligands 6,12-diformylindolo[3,2-b]carbazole and
6-formylindolo[3,2-b]carbazole provides the necessary basis for further
mechanistic studies of this important group of compounds, and will help in
determining the natural role of the Ah receptor.
|
