Ertl, J. | bioRxiv Science

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

BRAT1 - a new therapeutic target for glioblastoma

Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of protein breast cancer type 1 susceptibility protein (BRCA1)-associated Ataxia telangiectasia mutated (ATM)-activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic analyses further emphasize the role of BRAT1s cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments.

cancer biology↗