Biology subjects

Yeroslaviz, A.

Publications and source records attributed to Yeroslaviz, A..

9 recordsLinked to original sources

bioRxiv2026

Autoinducer-2 functions as both a quorum sensing and metabolic signal in Escherichia coli

Bacteria integrate diverse environmental signals to coordinate behavior, yet the relationship between nutrient sensing and quorum sensing (QS) remains incompletely understood. Autoinducer-2 (AI-2) is unique among QS signals in that its production is tightly linked to central metabolism, raising fundamental questions about the boundary between metabolic and signaling functions. In Escherichia coli, AI-2 coordinates collective behaviors through the lsr operon, whose expression is controlled not only by the AI-2-responsive repressor LsrR but also by the cAMP receptor protein (CRP), placing it at the intersection of carbon sensing and population-level signaling. While inhibition of lsr operon expression by PTS sugars such as glucose was previously established, we demonstrate that non-PTS sugars similarly suppress lsr expression through CRP, further decoupling QS activation from cell density and coupling it to carbon source availability. Systematic analysis of Enterobacteriaceae genomes reveals that CRP binding sites in the lsr promoter region are broadly conserved, indicating that metabolic modulation of AI-2 signaling is an ancestral regulatory feature. Importantly, using a FRET-based biosensor, we show that AI-2 uptake modulates intracellular cAMP levels in a manner resembling non-PTS carbon source transport, suggesting that AI-2 may have originally functioned as a nutrient substrate, with its signaling role emerging subsequently or co-evolving alongside. In support of this hypothesis, we isolated soil- and phyllosphere-associated bacteria capable of utilizing AI-2 as a sole carbon source. Our findings reveal an underappreciated metabolic dimension of AI-2 QS and suggest an evolutionary trajectory in which AI-2 signaling emerged from ancestral carbon utilization pathways. ImportanceQS allows bacteria to coordinate collective behaviors by detecting secreted signaling molecules, yet the evolutionary origins of these systems remain poorly understood. AI-2, one of the most broadly conserved bacterial signals, is derived from central metabolism and processed by machinery in E. coli that strikingly resembles a sugar utilization system. Here, we show that nutrient availability overrides cell density as the primary determinant of AI-2 responsiveness, that this regulatory logic is conserved among Enterobacteriaceae genomes, and that environmental bacteria can grow on AI-2 as a sole carbon source. These findings reframe AI-2 as a signal embedded within, and potentially evolved from, nutrient sensing pathways, with direct implications for understanding how byproducts of cellular metabolism can acquire signaling functions.

microbiology↗

bioRxiv2025

IL4i1-sourced oncometabolites promote neuroblastoma cell survival

High-risk neuroblastoma (NB) is driven by the amplification of MYCN in conjunction with additional oncogenic mutations in kinases such as ALK. NB cells require antioxidant responses to maintain redox balance and are highly sensitive to ferroptosis. Here, we show that metabolites derived from infiltrating immune cells expressing IL4i1, a secreted oxidoreductase, are potent suppressors of NB ferroptosis. IL4i1 metabolites (indole-3-pyruvate and 4-hydroxyphenylpyruvate) blocked ferroptosis in all human NB cell lines via a mechanism that depended on free radical scavenging and NRF2 activation but did not require the aryl hydrocarbon receptor. Supernatant transfer experiments confirmed that IL4i1 creates a milieu that protects NB cells from oxidative cell death. Importantly, mice lacking IL4i1 were protected from NB in a high-penetrance MYCN and mutant ALK-driven autochthonous cancer model. Therefore, we propose that immune IL4i1 is permissive for NB growth and survival. IL4i1 produces context-dependent oncometabolites and, as a secreted enzyme, represents a target for cell death manipulation in cancers sensitive to oxidative stress-driven cell death. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/669062v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@6e79baorg.highwire.dtl.DTLVardef@f9a9bcorg.highwire.dtl.DTLVardef@f6b2aaorg.highwire.dtl.DTLVardef@4bb764_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Single-cell metabolome and RNA-seq multiplexing on single plant cells

Plants produce valuable natural products used for a wide variety of industrial applications. Since these molecules have important applications in a variety of industrial sectors, there is enormous interest in elucidating the biosynthetic pathways that are responsible for the production of these compounds. Identification of the genes that comprise these biosynthetic pathways has been enabled by gene-to-metabolite networks that are generated from transcriptomic and metabolomic datasets. Recent advances in both single-cell RNA-seq (scRNA-seq) and single-cell mass spectrometry metabolomics (scMS) have enabled the measurement of either gene expression or metabolite levels in individual cells. However, these individual datasets can only be used to indirectly correlate gene expression levels with metabolite concentrations at the single cell level. Here we demonstrate that both scRNA-seq and scMS can be applied to the same plant cell, thereby enabling direct comparisons between gene expression and metabolite levels. This multiplexing approach reveals both qualitative and quantitative correlations between metabolite levels and biosynthetic gene expression in individual cells. This integrated approach sheds light on the underlying processes driving complex plant biosynthesis.

plant biology↗

bioRxiv2025

Differential cell survival outcomes in response to diverseamino acid stress

Amino acid (AA) detection is fundamental for cellular function, balancing translation demands, biochemical pathways, and signaling networks. While the GCN2 and mTORC1 pathways are known to regulate AA sensing, the global cellular response to AA deprivation remains poorly understood, particularly in non-transformed cells, which may exhibit distinct adaptive strategies compared to cancer cells. Here we employed murine pluripotent embryonic stem (ES) cells as a model system to dissect responses to AA stress. Using multi-omics analyses over an extended time course, we examined the effects of arginine (Arg) and leucine (Leu) deprivation and uncovered a broad array of proteomic, phosphoproteomic, transcriptomic, and metabolomic adaptations, including an increase in lysosome production, all occurring without lethality. We found that Arg or Leu starvation induces reversible cell cycle exit, promoting a quiescent state that enhances resistance to cytotoxic stressors. By contrast, cysteine (Cys) and threonine (Thr) deprivation led to cell death via distinct pathways: ferroptosis for Cys starvation, while Thr deprivation triggered a previously uncharacterized form of cell death, which could be entirely suppressed by methionine (Met) co-starvation, mTOR or translational inhibition. These findings suggest that ES cells implement specialized survival strategies in response to different AA limitations, highlighting their ability to reprogram cellular biochemistry under nutrient stress.

cell biology↗

bioRxiv2024

In-cell structure and snapshots of copia retrotransposons in intact tissue by cryo-electron tomography

Long terminal repeat (LTR) retrotransposons belong to the transposable elements (TE), autonomously replicating genetic elements that integrate into the hosts genome. LTR retrotransposons represent a major component of genomes across the tree of life; some derived sequences have even been domesticated by the host to perform cellular functions in essential processes such as development. Among animals, Drosophila melanogaster serves as an important model organism for TE research, harboring several LTR retrotransposons, including the Ty1-copia family, which is evolutionarily related to retroviruses and forms virus-like particles (VLPs). The architectural organization of copia VLPs in situ has remained unknown. In this study, we use cryo-FIB milling and lift-out approaches to visualize copia VLPs in isolated ovarian cells and intact egg chambers and resolve the in situ copia capsid structure to 7.7 [A] resolution by cryo-ET. While cytosolic copia VLPs vary in size, nuclear VLPs are homogenous and form densely packed clusters, supporting a model in which nuclear import acts as a size selector. By analyzing flies deficient in the TE-suppressing PIWI-piRNA pathway, we observe a change in copia localization from cytosolic to nuclear during spermatogenesis in testes. Our findings provide insights into the cellular structural biology of an active LTR retrotransposon and shed light on the replication cycle of copia in the context of host gametogenesis.

biophysics↗

bioRxiv2023

NF-κB c-REL-OTUD4 axis regulates B-cell receptor in B-cell lymphoma

The B-cell receptor (BCR) is essential for B-cell development and a crucial clinical target in immuno-oncology. However, therapeutic success against the BCR and downstream signaling pathways is hampered by enhanced NF-{kappa}B activation as a resistance mechanism. Using a multiomic approach, we discover the c-REL proto-oncogenic subunit of the NF-{kappa}B family as a key transcription factor regulating BCR subunit levels in B-cell lymphoma. Subsequent ChIP- seq, cell biology experiments, and patient data analysis reveal that OTUD4 is a critical deubiquitinase for inhibiting proteasomal degradation of c-REL and for stabilizing a multi-loop positive feedback of NF-{kappa}B to the BCR pathway. Remarkably, OTUD4 downregulation destabilizes c-REL and BCR levels and inhibits cell growth of B cell lymphoma. Thus, we shed light on the malignant potential of c-REL abundance, identify a positive feedback from c-REL to upstream BCR and present OTUD4 as a vulnerability to synergistically target NF-{kappa}B and BCR pathways in B-cell lymphoid malignancies.

cancer biology↗

bioRxiv2023

β1 integrin signaling governs necroptosis via the chromatin remodeling factor CHD4

Fibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. RIPK3, the central kinase of necroptosis signaling, is upregulated in fibrosis and contributes to the TNF-mediated inflammation. In bile duct ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of {beta}1 integrins, the major profibrotic ECM receptors in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via an epigenetic mechanism mediated by the chromatin remodeling factor CHD4. While the function of CHD4 has been conventionally linked to NuRD and ChAHP complexes, we found that CHD4 potently repressed a set of genes, including Ripk3, with high locus specificity but independent of either the NuRD or ChAHP complex. Thus, our data uncover that {beta}1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.

immunology↗

bioRxiv2020

Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion

The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin. We find that approximately 90% of the 299 suppressors and 86 enhancers identified are conserved in humans and that one third of the conserved genes have been implicated in human disease. Furthermore, many of the 385 genes have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. In addition, we find that enhancers are predominantly mitochondrial genes and suppressors non-mitochondrial genes, which indicates that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function that when disrupted can be compensated for by a variety of cellular processes. Our analysis of non-mitochondrial enhancers and mitochondrial suppressors suggests that organellar contact sites, especially between ER and mitochondria, are of importance for mitochondrial homeostasis. Finally, we uncovered several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants, found a potential link between pre-mRNA splicing and UPRmt activation and identified the Miga-1/2 ortholog K01D12.6 as required for mitochondrial dynamics in C. elegans.

cell biology↗

bioRxiv2017

Systematic transcriptomics reveals a biphasic mode of sarcomere morphogenesis in flight muscles regulated by Spalt

Muscles organise pseudo-crystalline arrays of actin, myosin and titin filaments to build force-producing sarcomeres. To study how sarcomeres are built, we performed transcriptome sequencing of developing Drosophila flight muscles and identified 40 distinct expression profile clusters. Strikingly, two clusters are strongly enriched for sarcomeric components. Temporal gene expression together with detailed morphological analysis enabled us to define two distinct phases of sarcomere development, which both require the transcriptional regulator Spalt major. During the sarcomere formation phase, 1.8 m long immature sarcomeres assemble myofibrils that spontaneously contract. During the sarcomere maturation phase, these sarcomeres grow to their final 3.2 m length and 1.5 m diameter and acquire stretch-sensitivity. Interestingly, the final number of myofibrils per flight muscle fiber is determined at the onset of the first phase. Together, this defines a biphasic mode of sarcomere and myofibril morphogenesis - a new concept that may also apply to vertebrate muscle or heart development.

developmental biology↗