Tryptophan Coordinates cGAS/STING Signaling in the Intestinal Epithelium

Inflammatory bowel disease (IBD) is characterized by a breakdown of the intestinal barrier function and a dysregulated inflammatory response to the microbiota for which currently no cure is available. Disease activity of IBD patients was previously found to negatively correlate with serum levels of the essential amino acid Tryptophan (Trp), which is known to play a regulatory role in the intestine and in immunity. Pathogens can be sensed via cyclic GMP-AMP synthase (cGAS) / stimulator of interferon genes (STING), an innate immune sensor complex involved in the detection of both foreign and self double-stranded DNA (dsDNA) resulting in type I interferon (IFN) production.
The present work shows that intracellular Trp differentially coordinates immune responses in enterocytes. In experiments employing the murine enterocytic cell line ModeK, it was shown that Trp starvation augmented the nuclear factor κB (NF-κB) activation upon lipopolysaccharide (LPS) or interleukin (IL)-1β stimulation. However, Trp starvation markedly impaired cGAS/STING activation and subsequent IFN I induction. This effect was attributed to a reduction in STING protein levels, which was dependent on protein translation.


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