Biology subjects

Koeberle, A.

Publications and source records attributed to Koeberle, A..

7 recordsLinked to original sources

bioRxiv2025

Host-specific platelet-activating factor acetylhydrolase selectively remodels diacylglycerophospholipids to control schistosome development

BackgroundSchistosomiasis, a major neglected tropical disease, is currently treated with only one drug, praziquantel (PZQ), effective only against adult worms. However, high reinfection rates and potential development of drug resistance following widespread use of PZQ emphasize the need for a deeper molecular understanding of the host-parasite crosstalk as a basis for urgently needed novel drugs. Here, we identify and characterize a soluble host-derived schistosomicidal phospholipase that influences the diacylglycerophospholipid metabolism and, thereby, the survival and development of Schistosoma mansoni. MethodsLarge-scale proteomic screening identified host platelet-activating factor acetylhydrolase (PAFAH) as a potential schistosomicidal factor. Ultra-performance tandem mass spectrometry and electron microscopy imaging were employed to demonstrate the relevance and the lethal effects of recombinant expressed mouse PAFAH (MsPAFAH) on all juvenile stages and adult parasites from a mouse model of schistosomiasis. Quantitative lipidomic analysis revealed MsPAFAH-impaired glycerophospholipid distribution and metabolism and following free fatty acid supplementation. ResultsMsPAFAH was upregulated in schistosome-infected mice and exhibited potent schistosomicidal activity against all parasite life stages ex vivo. In contrast, human PAFAH had no effect on parasite viability. MsPAFAH treatment led to profound impairments in worm fecundity, pairing stability, reproductive organ integrity, and stem cell development. This activity was associated with substantial sex-dependent changes in ether-phospholipid composition and distribution within the schistosome tegument. MsPAFAH specifically decreased the availability of phospholipid species containing unsaturated fatty acids, namely eicosenoic (20:1) and docosatetraenoic acid (22:4), while increasing levels of respective hydrolysis (lyso) products of diacyl- and ether-phospholipids (carrying 20:1 or stearic acid (18:0)), predominantly in males. Supplementation of metabolized fatty acids C20:1/eicosenoic acid and 22:4/adrenic acid rescued the viability of female worms, confirming the essential role of the metabolism of these diacylglycerophospholipids in schistosome survival. ConclusionsThese findings unravel how a host phospholipase interferes with schistosome biology and development by regulating diacylglycerophospholipid availability and can thus open new avenues for schistosomiasis drug development and control.

systems biology↗

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↗

bioRxiv2024

Silybin A from Silybum marianum reprograms lipid metabolism to induce a cell fate-dependent class switch from triglycerides to phospholipids

Silybum marianum is used to protect against degenerative liver damage. The molecular mechanisms of its bioactive component, silybin, remained enigmatic, although membrane-stabilizing properties, modulation of membrane protein function, and metabolic regulation have been discussed for decades. Here, we show that specifically the stereoisomer silybin A decreases triglyceride levels and lipid droplet content, while enriching major phospholipid classes and maintaining a homeostatic phospholipid composition in human hepatocytes in vitro and in mouse liver in vivo under normal and pre-disease conditions. Conversely, in cell-based disease models of lipid overload and lipotoxic stress, silybin treatment primarily depletes triglycerides. Mechanistically, silymarin/silybin suppresses phospholipid-degrading enzymes, induces phospholipid biosynthesis to varying degrees depending on the conditions, and down-regulates triglyceride biosynthesis, while inducing complex changes in sterol and fatty acid metabolism. Structure-activity relationship studies highlight the importance of the 1,4-benzodioxane ring configuration of silybin A in triglyceride reduction and the saturated 2,3-bond of the flavanonol moiety in phospholipid accumulation. Enrichment of hepatic phospholipids and intracellular membrane expansion are associated with an heightened biotransformation capacity. In conclusion, our study deciphers the structural features of silybin contributing to hepatic lipid reorganization and offers insights into its liver-protective mechanism, potentially involving a context-dependent lipid class switch from triglycerides to phospholipids.

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↗

bioRxiv2022

Proteome coverage after simultaneous proteo-metabolome liquid-liquid extraction

Proteo-metabolomics is essential in systems biology and simultaneous proteo-metabolome extraction by liquid-liquid extraction (SPM-LLE) allows extraction of the metabolome and proteome from the same sample. Since the proteome is present as a pellet in SPM-LLE it must be solubilized for quantitative proteomics. Solubilization and proteome extraction is a critical factor in the information that can be obtained at the proteome level. In this study, we investigated the performance of two surfactants (sodium deoxycholate (SDC), sodium dodecyl sulfate (SDS)) and urea with respect to proteome coverage and extraction efficiency of an interphase proteome pellet generated by methanol-chloroform based SPM-LLE. We also investigated the extent to which the performance differs when the proteome is extracted from the interphase pellet or by direct cell lysis. Our study reveals that the proteome coverages between the two surfactants and urea for the SPM-LLE interphase pellet were very similar, but the extraction efficiencies differed significantly. While SDS led to enrichment of basic proteins, which were mainly ribosomal and ribonuclear proteins, urea was the most efficient extraction agent for simultaneous proteo-metabolome analysis. The results of our study also show that the performance of surfactants (SDC, SDS) for quantitative proteomics is better when the proteome was extracted by direct cell lysis and not from an interphase pellet. In contrast, the performance of urea for quantitative proteomics was significantly better when the proteome was extracted from an interphase pellet and by direct cell lysis.

systems biology↗

bioRxiv2019

Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.

The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented. HighlightsO_LILate life metformin treatment limits cell survival and shortens lifespan. C_LIO_LIMetformin exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion. C_LIO_LIOld cells fail to upregulate glycolysis as a compensatory response to metformin. C_LIO_LIThe dietary restriction (DR) mimetic response to metformin is abrogated in old animals. C_LIO_LIPKA and not AMPK pathway instigates the early life DR response to metformin. C_LIO_LIStabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. C_LI

physiology↗

bioRxiv2019

TRiC activates the unfolded protein response and protects starved stem cells by modulating energy and lipid metabolism during planarian regeneration

Fasting protects stem cells and increases stem cell functionality through mechanisms which are not fully understood. Planarians are not only able to regenerate their bodies, but also to stand long periods of starvation by shrinking in size. This adaptation is possible because of a large population of adult stem cells which indefinitely self-renew even under starved conditions and thus confer planarians with immortality. How starved planarians are able to maintain healthy stem cells and to fuel stem cell proliferation allowing regeneration is unknown. Here we found the TCP-1 ring complex (TRiC) to be upregulated in starved stem cells. Down-regulation of TRiC impairs planarian regenerative response by inducing stem cell genome instability, mitotic defects and stem cell death which translates into stem cell exhaustion. This regulation is specific of starvation since feeding planarians prevents the phenotype. Importantly we found that TRiC activates the unfolded protein response (UPR) which allows a convergent regulation of cellular energy and lipid metabolism in starved planarians thus permitting the high energy demanding regenerative mitotic response. We identified a novel mechanism through which starvation protects the somatic stem cell genome allowing for unlimited stem cell proliferation and regeneration.

developmental biology↗