Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad-spectrum antifungal activity

Zhou, Y.; Zhao, J.; Yang, L.; Bi, R.; Qin, Z.; Sun, P.; Li, R.; Zhao, M.; Wang, Y.; Chen, G.; Wan, H.; Zheng, L.; Wang, G.; Chen, X.-L.; Li, Q.; Li, G.

doi:10.1101/2023.04.07.535992

bioRxiv · 10.1101/2023.04.07.535992

Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad-spectrum antifungal activity

Zhou, Y.·Zhao, J.·Yang, L.·Bi, R.·Qin, Z.·Sun, P.·Li, R.·Zhao, M.·Wang, Y.·Chen, G.·Wan, H.·Zheng, L.·Wang, G.·Chen, X.-L.·Li, Q.·Li, G.

View original source ↗Export metadata ↓

Abstract

O_LIAs phospholipids of cell membranes, phosphatidylethanolamine (PE) and phosphatidylserine (PS) play crucial roles in glycerophospholipid metabolism. Broadly, some phospholipid biosynthesis enzymes serve as potential fungicide targets. Therefore, revealing the functions and mechanism of PE biosynthesis in plant pathogens would provide potential targets for crop disease control. C_LIO_LIWe performed analyses including phenotypic characterizations, lipidomics, enzyme activity, site-directed mutagenesis, and chemical inhibition assays to study the function of PS decarboxylase-encoding gene MoPSD2 in rice blast fungus Magnaporthe oryzae. C_LIO_LIThe Mopsd2 mutant was defective in development, lipid metabolism and plant infection. The PS level increased while PE decreased in Mopsd2, consistent with the enzyme activity. Furthermore, chemical doxorubicin inhibited the enzyme activity of MoPsd2 and showed antifungal activity against ten phytopathogenic fungi including M. oryzae and reduced disease severity of two crop diseases in the field. Three predicted doxorubicin-interacting residues are important for MoPsd2 functions. C_LIO_LIOur study demonstrates that MoPsd2 is involved in de novo PE biosynthesis and contributes to the development and plant infection of M. oryzae and that doxorubicin shows broad-spectrum antifungal activity as a fungicide candidate. The study also implicates that bacterium Streptomyces peucetius, which biosynthesizes doxorubicin, could be potentially used as an eco-friendly biocontrol agent. C_LI

Source connections

Published article ↗

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Zhou, Y., Zhao, J., Yang, L., Bi, R., Qin, Z., Sun, P., Li, R., Zhao, M., Wang, Y., Chen, G., Wan, H., Zheng, L., Wang, G., Chen, X.-L., Li, Q., Li, G.. 2023-04-08. Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad-spectrum antifungal activity. https://doi.org/10.1101/2023.04.07.535992

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗

bioRxiv2023

Aberrant connective tissue sheath contraction drives premature hair follicle regression by inducing progenitor cell depletion in androgenetic alopecia

Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair, forming a distinctive patterned baldness in the scalp; yet, the mechanisms for hair miniaturization in this disease remain largely unknown. Here by single-cell transcriptome analysis, we describe a concise single-cell atlas, and identify the early changes in cell subpopulations, hair follicle (HF) stem cell fate determination and cell-cell communications in AGA anagen HF units. Thereinto, apoptotic loss of HF progenitor cells is significantly increased, correlated with HF miniaturization in AGA. Mechanistically, enhanced contraction of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1, which triggers ectopic apoptosis of progenitor cells in human anagen HFs. Continuous CTS contraction during AGA causes long-term loss of progenitor cells via inducing persistent ectopic apoptosis through PIEZO1, eventually leading to premature hair regression. Most importantly, we show that targeting CTS contraction by ML-7, a selective myosin light chain kinase (MLCK) inhibitor, can obviously improve the growth of HFs from balding scalps of AGA patients. Our study reveals the cellular hierarchies and identifies CTS with increased muscle contraction activity as a driver of premature hair regression in AGA, highlighting CTS surrounding human HF as the therapeutic target for treating this disorder.

pathology↗

bioRxiv2023

Optimization of neuromuscular blockade protocols in cynomolgus macaques: monitoring, doses and antagonism

BackgroundNeuromuscular blocking agents (NMBAs) are a crucial component of anaesthesia and intensive care. NMBAs are a family of molecules defined by their ability to compete with acetylcholine for binding to the acetylcholine receptor at the neuromuscular junction. This functional homology relies on the presence of ammonium groups in all NMBAs that, however, display vastly different chemical structures. Among animal models, non-human primates (NHP) are an essential model for a great diversity of human disease models but remain poorly characterized for the effectiveness of the diverse NMBAs. MethodsSeven healthy male cynomolgus macaques were randomly assigned to this study. Experiments using macaques were approved by the local ethical committee (CEtEA #44). All animals were anaesthetized according to institutional guidelines, with ketamine and medetomidine, allowing IV line placement and tracheal intubation. Anaesthesia was maintained with isofluorane. Either rocuronium bromine or atracurium besylate was evaluated, with reversal with sugammadex. Monitoring was performed with two devices, TOF-Watch(R) and ToFscan(R), measuring the T4/T1 and the T4/Tref ratios, respectively. Nonparametric Mann-Whitney statistical analyses were done when indicated. ResultsNMBA monitoring required adaptation compared to humans, such as stimulus intensity and electrodes placement, to be efficient and valid in Cynomolgus macaques. When administered, both NMBAs induced deep and persistent neuro-muscular blockade at equivalent doses to clinical doses in humans. Rocuronium-induced profound neuromuscular blockade could be reverted using the cyclodextrin sugammadexs reversal agent. We report no adverse effects in these models by clinical observation, blood chemistry, or complete blood count. ConclusionThese results support the use of non-human primate models for neuromuscular blockade monitoring and testing novel NMBA or their reversal agents.

pathology↗