Category Archives: Innate defense

At least a bacterial ligand for the ArH

The aryl hydrocarbon receptor ArH is a nuclear receptor and as such a transcription factor which has been shown to be activated by dioxins and other environmental toxins. Upon ligand binding it is translocated to the nucleus, binds dioxin responsive elements on the DNA, and triggers gene activation notably of CYP 1 monoxygenases, which in turn degradate dioxins to more soluble compounds thus facilitating their removal. It not only binds dioxins, but polyaromatic substances like benzopyrenes in tobacco smoke and a variety of plant substances like e.g. indigo.

Its structure as basic helix loop helix (bHLH) protein has been determined.

It has been questionable how a molecule with such a ligand profile has survived evolution. Groups from Berlin have now determined bacterial secondary products as ligands of the receptor, too. In a paper in Nature this week they describe Pseudomonas aeruginosa phenazines and Mycobacterium tuberculosis phthiols as ligands which activate anti-bacterial responses in mice. This role makes much more sense in terms of evolution. It would be more beneficial to have the protein than not to have it. Nicely done.

Caspases 4, 5 and 11 are Intracellular LPS Receptors

A LPS receptor has already been identified by Beutler and colleagues. This finding was awarded the NOBEL prize in 2011. In the actual issue of Nature (doi:10.1038/nature13683) Shi and colleagues describe the role of caspases – enzymes triggerung cell death called apoptosis – as intracellular receptors for LPS.

When LPS is delived intracellarly into macrophages, epithelial cells or keratinocytes these cells undergo necrosis. The process is specific for intact Lipid A. Murine caspase-11 as well as human caspases 4 and 5 bind to LPS and Lipid A. They induce what is called pyroptosis. The paper is nicely done, however, one might wonder when and how LPS is released from the phagolysosome and becomes available within a cell.

LPS tolerance, aryl hydrocarbon receptor and dioxygenases

Yesterday I saw a fascinating Nature article (Nature doi:10.1038/nature13323): Low doses of LPS in mice induce LPS tolerance. The underlying mechanism involve – according to the authors – the AhR and two different dioxigenases, tryptophan 2,3-dioxygenase and  indoleamine 2,3-dioxygenase. This is related to endotoxic shock a still devasting condition.