Biology subjects

Balogh, G.

Publications and source records attributed to Balogh, G..

7 recordsLinked to original sources

bioRxiv2026

A preclinical resistance framework discovers the virulence risks of antibiotics in development

Several new antibiotics target multidrug-resistant pathogens, yet resistance is still evaluated mainly by drug-susceptibility, leaving consequences for bacterial pathogenicity poorly understood. Here, we develop a framework integrating resistance evolution, genomic surveillance and host-pathogen phenotyping to classify antibiotics by resistance potential and pathogenic consequences. Applying this framework to Klebsiella pneumoniae identified functionally distinct antibiotic candidates associated with elevated virulence risk. Resistance evolution rapidly increased virulence through clinically-relevant mutations, without direct selection for pathogenicity. Despite distinct genetic routes, resistance converged on cell-envelope rewiring. A single resistance mutation increased epithelial adhesion, intracellular colonization, macrophage immune-evasion, and tissue persistence in murine infection models, transforming K. pneumoniae into a more invasive and cytotoxic pathogen. Risk-profile analysis revealed partial decoupling of resistance and pathogenicity, with some low-resistance antibiotics yielding highly-virulent populations. These findings establish resistance-driven virulence as an underappreciated translational hazard and call for incorporating host-pathogen interactions into resistance surveillance and preclinical antibiotic development.

microbiology↗

bioRxiv2025

Adaptation of eukaryotic membrane homeostasis to species-specific cellular lipid landscapes

The physicochemical properties of biological membranes must be maintained within a range compatible with cellular physiology. In the face of external perturbations, membrane lipid homeostasis mechanisms sense and control membrane features. How such mechanisms evolve to function in organisms with different cellular lipid make-up is unknown. Here, we address this fundamental question by exploiting the natural divergence in membrane lipid composition between the related fission yeasts S. pombe and S. japonicus. Using lipidomics and transcriptomics, we show that the activity of the membrane-bound transcriptional activator Mga2, which regulates the {Delta}-9 desaturase Ole1 expression, is set to sense distinct levels of membrane unsaturation in the two species. Through retro-engineering and physiological experiments, we identify an evolutionary divergent but functionally constrained element within the juxtamembrane region of Mga2, which fine-tunes its performance to species-specific lipid composition. Our experiments indicate that high baseline expression of ole1, set by cis-regulatory elements in its upstream non-coding region, has redefined the dynamic range of Mga2 activation in S. pombe, supporting high lipidome unsaturation. Our work explores an "experiment of nature" to highlight the broad principles underlying the organisation and evolution of membrane homeostasis, which should be applicable to other genetic networks supporting cellular homeostatic processes.

cell biology↗

bioRxiv2025

Fatty acid synthesis supports tumor progression through keeping TORC1 receptive for Insulin/PI3K signaling

Biosynthesis of lipids and fatty acids (FAs) is a tightly regulated and complex process essential for the normal functioning of various cellular processes as is sufficient lipid availability for the progression of several malignant tumor types. Despite its importance, the roles of the individual steps in lipid biosynthesis during tumor growth and their subsequent interaction with intracellular signaling pathways are still not well understood. In our study, we used the RasV12, Scribble deficient carcinoma model in Drosophila to demonstrate that upregulation of de novo FA and lipid synthesis is a conserved characteristic of malignant tumors. Performing a small-scale genetic screen by tumor cell specific silencing of components of neutral lipid biosynthetic apparatus revealed that the loss of several enzymes involved in FA and diacylglycerol synthesis significantly inhibited tumor growth. Further characterization of the role of acetyl-CoA carboxylase (ACC), the enzyme responsible for the first step of FA synthesis, revealed that loss of ACC significantly reduced late-stage tumor growth due to increased apoptotic activity. However, early tumor development was unaffected. This correlated with our observation that perturbation of FA synthesis led to inactivation of TORC1 (Target of Rapamycin Complex 1) - the master regulator of cell growth and survival - accompanied by activation of the catabolic process autophagy. Moreover, we also demonstrated that TORC1 activity cannot be restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC deficient tumor cells but supplementation of ACC deficient tumors with ectopically added oleic acid alone could improve TORC1 activity and thereby tumor progression. Hence, our findings highlight a new role of FAs in regulating TORC1, rendering it receptive to upstream activatory signals, explaining why cancer cells are extremely dependent on de novo FA synthesis.

cell biology↗

bioRxiv2024

Horizontal gene transfer-initiated reorganization of lipid metabolism drives lifestyle innovation in a eukaryote

Horizontal gene transfer is a source of metabolic innovation and adaptation to new environments. Yet, how horizontally transferred metabolic functionalities are integrated into host cell biology remains an open question. Here, we use the fission yeast Schizosaccharomyces japonicus to probe how eukaryotic lipid metabolism is rewired in response to the acquisition of a horizontally transferred squalene-hopene cyclase Shc1. We show that Shc1-dependent production of hopanoids, the structural mimics of eukaryotic sterols, allows S. japonicus to thrive in anoxia, where sterol biosynthesis is not possible. We further demonstrate that glycerophospholipid fatty acyl asymmetry, prevalent in S. japonicus, is crucial for accommodating both sterols and hopanoids in membranes, and explain how Shc1 functions alongside the native sterol biosynthetic pathway to support membrane properties. Through engineering experiments in the sister species S. pombe, which naturally lacks Shc1, we show that the acquisition of Shc1 may entail new physiological traits; however, to maximize Shc1 performance, sterol biosynthesis must be dampened. Our work sheds new light on the mechanisms underlying cellular integration of horizontally transferred genes in eukaryotes and provides broader insights into the evolution of membrane organization and function.

cell biology↗

bioRxiv2024

Mild hyperthermia-induced thermogenesis in the endoplasmic reticulum defines stress response mechanisms

Previous studies reported that a mild, non-protein denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells. Temperatures reached at least 8{degrees}C higher than the external environment (40{degrees}C), resulting in exceptionally high ER temperatures similar to those previously described for mitochondria. Mild heat-induced thermogenesis in the ER of MEF cells was likely due to the uncoupling of the Ca2+/ATPase (SERCA) pump. The high ER temperatures initiated a pronounced cytosolic heat shock response in MEF cells, which was significantly lower in U2OS cells in which both the ER thermogenesis and SERCA pump uncoupling were absent. Our results suggest that, depending on intrinsic cellular properties, mild hyperthemia-induced intracellular thermogenesis defines the cellular response mechanism, and determines the outcome of hyperthermic stress.

cell biology↗

bioRxiv2020

Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumour immunity

The human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a much wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response is unknown. In this paper, we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles, and found that cancer patients that carry HLA-I alleles with high peptide binding promiscuity are characterized by significantly worse prognosis after immune checkpoint inhibitor treatment. This trend can be explained by a reduced capacity of promiscuous HLA-I molecules to discriminate between human self and tumour peptides, yielding a shift in regulation of T-cells in the tumour microenvironment from activation to tolerance. In summary, HLA-I peptide binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner. It could also underlie a negative trade-off between antitumour immunity and the genetic susceptibility to viral infections.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2019

Delineating the rules for structural adaptation of membrane-associated proteins to evolutionary changes in membrane lipidome

Membrane function is fundamental to life. Each species explores membrane lipid diversity within a genetically predefined range of possibilities. How membrane lipid composition in turn defines the functional space available for evolution of membrane-centered processes remains largely unknown. We address this fundamental question using related fission yeasts Schizosaccharomyces pombe and Schizosaccharomyces japonicus. We show that unlike S. pombe that generates membranes where both glycerophospholipid acyl tails are predominantly 16-18 carbons long, S. japonicus synthesizes unusual asymmetrical glycerophospholipids where the tails differ in length by 6-8 carbons. This results in stiffer bilayers with distinct lipid packing properties. Retroengineered S. pombe synthesizing the S. japonicus-type phospholipids exhibits unfolded protein response and downregulates secretion. Importantly, our protein sequence comparisons and domain swap experiments indicate that transmembrane helices co-evolve with membranes, suggesting that, on the evolutionary scale, changes in membrane lipid composition may necessitate extensive adaptation of the membrane-associated proteome.

cell biology↗