Waltl, L. | bioRxiv Science

bioRxiv2024

Reorganization of innate immune cell lipid profiles by bioinspired meroterpenoids to limit inflammation

Lipidomics-guided screening of unexplored chemical space in natural products provides access to small molecules capable of modifying cellular lipid profiles on a global scale. Here, we show that the meroterpenoid cyclosmenospongine from Spongia sp. shapes the lipid profile of immune cells, favoring anti-inflammatory and pro-resolving over pro-inflammatory lipid mediators. Structural variation revealed derivatives that inhibit leukotriene biosynthesis to varying extents while differentially upregulating pro-resolving lipid mediators, epoxyeicosatrienoic acids, endocannabinoids, and sphingosine-1-phosphate, along with other mediators, both in resting and activated innate immune cells in vitro and in self-resolving murine peritonitis in vivo. Mechanistically, meroterpenoids target 5-lipoxygenase or 5-lipoxygenase-activating protein, promote the translocation of 15-lipoxygenase-1 to cytoplasmatic sites, and inhibit monoacylglycerol lipase. They also redirect arachidonic acid (AA) from neutral lipids to specific phospholipids, while increasing the total concentration of free AA. Furthermore, meroterpenoids reprogram lipid metabolism in immune cells, decreasing the levels of neutral lipids, triacylglycerols, and cholesteryl esters. This shift correlates with a reduced capacity for leukotriene biosynthesis and is mimicked by the inhibition of sterol-O-acyltransferase and diacylglycerol acyltransferase-1/2. In conclusion, specific meroterpenoids exert anti-inflammatory effects by intervening in lipid mediator biosynthesis, prompting structure-controlled switches in lipid mediator classes, among others, through an unexpected link between lipogenesis and inflammation.

pharmacology and toxicology↗

bioRxiv2023

Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy

Tumours face tryptophan (Trp) depletion, but the mechanisms sustaining protein biosynthesis under Trp stress remain unclear. We report that Trp stress increases the levels of the translation repressor EIF4EBP1. Yet, at the same time, EIF4EBP1 is selectively phosphorylated by the metabolic master regulator MTORC1 kinase, preventing EIF4EBP1 from inhibiting translation. MTORC1 activity under Trp stress is unexpected because the absence of amino acids is typically linked with MTORC1 inhibition. EIF4EBP1-sensitive translation in Trp starved cells is sustained by EGFR and RAS signalling to MTORC1. Via this mechanism, Trp stress enhances the synthesis and activity of the aryl hydrocarbon receptor (AHR). This is noteworthy as Trp catabolites are known to activate AHR, and therefore Trp stress was previously considered to inhibit AHR. Trp stress-induced AHR enhances the expression of key regulators of autophagy, which sustains intracellular Trp levels and Trp-charged tRNAs for translation. Hence, Trp stress switches MTORC1 from its established inhibitory function into an enhancer of autophagy, acting through AHR. The clinical potential of this fundamental mechanism is highlighted by the activity of the mTORC1-AHR pathway and an autophagy signature in 20% of glioblastoma patients, opening up new avenues for cancer therapy.

biochemistry↗