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At least 829 records · Page 46Linked to original sources

bioRxiv2024

Microsporidian Nosema bombycis secretes serine protease inhibitor to suppress host cell apoptosis via caspase BmICE

Microsporidia are a group of intracellular pathogens that actively manipulate host cell biological processes to facilitate their intracellular niche. Apoptosis is an important defense mechanism by which host cell control intracellular pathogens. Microsporidia modulating host cell apoptosis has been reported previously, however the molecular mechanism is not yet clear. In this report, we describe that the microsporidia Nosema bombycis inhibits apoptosis of Bombyx mori cells through a secreted protein NbSPN14, which is a serine protease inhibitor (Serpin). An immunofluorescent assay demonstrated that upon infection with N. bombycis, NbSPN14 was initially found in the B. mori cell cytoplasm and then became enriched in the host cell nucleus. Overexpression and RNA-interference (RNAi) of NbSPN14 in B. mori embryo cells confirmed that NbSPN14 inhibited host cell apoptosis. Immunofluorescent and Co-IP assays verified the co-localization and interaction of NbSPN14 with the BmICE, the caspase 3 homolog in B. mori. Knocking out of BmICE or mutating the BmICE-interacting P1 site of NbSPN14, eliminated the localization of NbSPN14 into the host nucleus and prevented the apoptosis-inhibiting effect of NbSPN14, which also proved that the interaction between BmICE and NbSPN14 occurred in host cytoplasm and the NbSPN14 translocation into host cell nucleus is dependent on BmICE. These data elucidate that N. bombycis secretory protein NbSPN14 inhibits host cell apoptosis by directly inhibiting the caspase protease BmICE, which provides an important insight for understanding pathogen-host interactions and a potential therapeutic target for N. bombycis proliferation. Author SummaryMicrosporidia constitute a class of eukaryotic pathogens that exclusively reside within host cells. The species Nosema bombycis is the first microsporidian identified as the pathogen of silkworm Pebrine disease. In our research, we discovered how N. bombycis cleverly evades the hosts defenses. It has developed a strategy to survive inside host cells by manipulating host cell apoptosis, disarming the host cells self-destruct mechanism. In this study, we discovered that the N. bombycis secretes a serine protease inhibitor named NbSPN14, which infiltrates the cytoplasm of the host cell. The NbSPN14 interacts with the executioner Caspase protease BmICE within the silkworms apoptotic pathway, effectively neutralizing its apoptoic activity and thus curbing the apoptosis of the host cells.

microbiology↗

bioRxiv2024

Translation components in adult Drosophila melanogaster adipocytes regulate the ovarian germline stem cell lineage

Adult stem cells, which support tissue homeostasis and damage repair, are influenced by whole organism physiology. Dietary input has a major impact on the stem cell supported ovary in Drosophila melanogaster females, appropriately matching reproductive output to nutrient availability. Previous work has shown that inter-organ communication plays a role in modulating the ovarian response to diet. Specifically, amino acid sensing by the adipose tissue remotely controls germline stem cells and their progeny. While we have shown that activation of the amino acid response pathway, a part of the integrated stress response, and mTOR signaling in adipocytes impacts germline stem cell maintenance and ovulation, it is unclear how downstream signaling mediates these responses. Here, using a combination of genetic and cell biological tools, we show that regulation of translation in adult adipocytes impacts the ovarian germline stem cell lineage, from stem cell maintenance to ovulation of mature oocytes. This work strongly suggests that the adipose tissue produces specific factors to control stem cell activity in the ovary and highlights how inter-organ communication underlies organismal physiological responses to diet.

physiology↗

bioRxiv2025

The ribosomal protein RPS6A modulates auxin signalling and root development in Arabidopsis

Protein biosynthesis by the ribosome is a fundamental biological process in living systems. Recent studies suggest that ribosomal subunits also play essential roles in cell growth and differentiation beyond their roles in protein translation. The ribosomal subunit RPS6 has been studied for more than 50 years in various organisms, but little is known about its specific roles in a certain signalling pathway. In this study, we focused on the functions of Arabidopsis RPS6A in auxin-related root growth and development. The rps6a mutant exhibited a series of auxin-deficient phenotypes, such as shortened primary root length, reduced lateral root number, and defective vasculatures. Treatment of the rps6a mutant with various concentrations of auxin and its analogues did not restore the root defect phenotype, suggesting a defect in the auxin signalling pathway. Further cell biological and global transcriptome analyses revealed that auxin signalling was weakened in the rps6a mutant and that there was a reduced abundance of PIN-FORMED (PIN) auxin transporters. Our work provides insights into the role of the protein biosynthesis pathway involved in auxin signalling.

plant biology↗

bioRxiv2026

Primary cilia coordinate c-KIT signaling induced proliferation in alpha cells

Circulating glucagon levels are elevated in patients with diabetes and obesity and contribute to hyperglycemia. The mechanisms underlying hyperglucagonemia remain poorly understood, but expansion of pancreatic -cell mass is thought to play an important role. Primary cilia are sensory organelles that act as signaling hubs, for pathways controlling cell differentiation, proliferation, and function, yet their contribution to -cell biology remains poorly defined. Here we investigated the role of primary cilia in the regulation of -cell proliferation. To this end we generated the first -cell primary cilia proteome identifying 167 cilia-enriched proteins. Among these, we identified and validated the proto-oncogene receptor tyrosine kinase, c-KIT, as a novel ciliary receptor in -cells. We further show that c-KIT signaling depends on intact primary cilia and that stimulation of isolated mouse islets with its endogenous ligand, stem cell factor (SCF), promotes -cell proliferation. In human pancreatic islets KITLG mRNA expression, but not KIT mRNA expression, correlated positively with donor BMI, suggesting that increased ligand availability drives c-KIT signaling in obesity. Together, our findings identify the primary cilium as a signaling platform c-KIT in cells and reveal a ciliary axis that may drive -cell expansion and hyperglucagonemia in obesity and diabetes.

physiology↗

bioRxiv2026

Asymmetric division and polar growth define a non-canonical cell cycle in Bradyrhizobium.

Bradyrhizobia are widely used as plant growth promoters in agriculture, yet their cell biology remains poorly understood. Here, we described for the first time, nucleoid segregation dynamics and the cell cycle of Bradyrhizobium at the cellular level. We show that highly asymmetric polar growth generates a short daughter cell and a longer mother cell at each division. Nucleoid compaction and positioning change across growth phases, culminating in a highly compacted, asymmetrically positioned nucleoid in stationary phase. ParB presents a subpolar localization, at the nucleoid periphery. Despite this pronounced cellular asymmetry and the presence of a single large chromosome, chromosome conformation capture reveals a global chromosome organization similar to that of bacteria undergoing conventional binary fission Together, these findings uncover a distinctive cell cycle program in Bradyrhizobium. showing that such extreme asymmetry in growth and division, significantly different from closely related characterized -Proteobacteriota, is compatible with conserved principles of chromosome organization.

microbiology↗

bioRxiv2025

Single cell-derived spheroids for real-time growth and metabolomic studies in breast cancer

Breast cancer remains a leading cause of cancer-related mortality, with disease progression and metastasis posing significant challenges in treatment. Three-dimensional (3D) cancer models have emerged as valuable tools for studying cancer cell biology in a physiologically relevant microenvironment. Studying the tumour heterogeneity and metabolic adaptations at the single-cell level can be crucial to identify factors driving metastatic progression. Here, we present a novel approach to generate single cell-derived breast cancer spheroids using cell lines (MCF-7 and MCF-10A) within a decellularised adipose tissue extracellular matrix (adECM). Spheroid culture conditions were optimised with integrated plasmonic nanosensors (gold nanostars - GNSs), to enable real-time surface-enhanced Raman scattering (SERS)-based measurements. Our results demonstrated that spheroid growth kinetics and viability in adECM were comparable to commonly used animal-derived matrices, validating its use as a reproducible ECM hydrogel. We further show that the concentration of plasmonic nanosensors used was compatible with cell culture and enabled SERS detection of a model reporter, paving the way for label-free, non-destructive analysis of cancer cell metabolism. This platform offers a promising approach to study cancer progression, including metabolic adaptations, with potential applications in biomarker discovery and preclinical research.

cancer biology↗

bioRxiv2018

Drosophila anion exchanger 2 is required for proper ovary development and oogenesis

Understanding how cell fate decisions are regulated is a central question in stem cell biology. Recent studies have demonstrated that intracellular pH (pHi) dynamics contribute to this process. Indeed, the pHi of cells within a tissue is not simply a consequence of chemical reactions in the cytoplasm and other cellular activity, but is actively maintained at a specific setpoint in each cell type. We found previously that the pHi of cells in the follicle stem cell (FSC) lineage in the Drosophila ovary increases progressively during differentiation from an average of 6.8 in the FSCs, to 7.0 in newly produced daughter cells, to 7.3 in more differentiated cells. Two major regulators of pHi in this lineage are Drosophila sodium-proton exchanger 2 (dNhe2) and a previously uncharacterized gene, CG8177, that is homologous to mammalian anion exchanger 2 (AE2). Based on this homology, we named the gene ae2. Here, we generated null alleles of ae2 and found that homozygous mutant flies are viable but have severe defects in ovary development and adult oogenesis. Specifically, we find that ae2 null flies have smaller ovaries, reduced fertility, and impaired follicle formation. In addition, we find that the follicle formation defect can be suppressed by a decrease in dNhe2 copy number and enhanced by the overexpression of dNhe2, suggesting that this phenotype is due to the dysregulation of pHi. These findings support the emerging idea that pHi dynamics regulate cell fate decisions and our studies provide new genetic tools to investigate the mechanisms by which this occurs.

developmental biology↗

bioRxiv2025

Basal cytoplasmic calcium levels regulate C. elegans germ stem cell proliferation

The C. elegans germline is one of the foremost model systems for the study of germ cell biology. We have created an integrated ratiometric calcium reporter that allows comparative analysis of calcium levels in germ cells. We observe a positive correlation between the rate of cell proliferation and calcium levels. Conditions that decrease proliferation decrease basal cytoplasmic calcium levels, these include starvation and loss of insulin, TGF-{beta}, and folate signaling. Conversely, overproliferating germline tumor cells have increased basal cytoplasmic calcium levels. To determine if basal calcium levels regulate the rate of proliferation, we decreased calcium levels by inactivating the TRPM7-related GON-2 calcium channel. A gon-2 null mutant has significantly decreased basal cytoplasmic calcium levels and germ cell proliferation. Partial reduction of GON-2 activity in a gon-2 mutant heterozygote also reduces calcium levels and proliferation, but to a lower extent. This identifies GON-2 as a calcium channel that is required to maintain basal cytoplasmic calcium levels in germ cells. Conversely, increasing basal cytoplasmic calcium levels in germ cells either by inhibiting the plasma membrane calcium ATPase (which transports cytoplasmic calcium out of cells) or by inhibiting the SERCA channel (which transports cytoplasmic calcium into the endoplasmic reticulum) increased basal calcium levels and germ cell proliferation. This study identifies the germ line as the first tissue in C. elegans whose rate of cell proliferation is regulated by calcium. While transient increases in calcium are associated with cell proliferation in many animal species, our study suggests that the basal level of cytoplasmic calcium acts as a rheostat to modulate the rate of C. elegans germ cell proliferation in response to physiological processes and signals.

developmental biology↗

bioRxiv2022

Cdk1-mediated threonine phosphorylation of Sam68 modulates its RNA binding, alternative splicing activity, and cellular functions

Sam68 is a member of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins and its role is modulated by post-translational modifications, including serine/threonine phosphorylation, that differ at various stages of the cell cycle. However, the molecular basis and mechanisms of these modulations remain largely unknown. Here, we combined mass spectrometry, NMR spectroscopy, and cell biology techniques to provide a comprehensive post-translational modification (PTM) mapping of Sam68 at different stages of the cell cycle in HEK293 and HCT116 cells. We established that Sam68 is specifically phosphorylated at T33 and T317 by Cdk1, and demonstrated that these phosphorylation events reduce the binding of Sam68 to RNA, control its cellular localization, and reduce its alternative splicing activity, leading to a reduction in the induction of apoptosis and an increase in the proliferation of HCT116 cells.

molecular biology↗

bioRxiv2026

Intrinsic regulation of intestinal stem cell fate and homeostasis by Tet

How developmental progenitors navigate divergent trajectories to either establish adult stem cell pools or undergo terminal differentiation remains a fundamental gap in stem cell biology. Here, we identify the well conserved Tet protein as an essential transcriptional regulator of intestinal stem cell (ISC) establishment. Developmental Tet depletion causes region-specific ISC loss and compromises adult lifespan, while adult-specific loss drives progressive stem cell exhaustion. Overexpression of Tet leads to ISC expansion in both developing and adult guts. Utilizing a comprehensive single-nucleus transcriptomic atlas spanning gut development, we demonstrate that Tet stabilizes progenitor identity by maintaining epithelial integrity, niche signaling, and fate maintenance. By defining this developmental trajectory, we reveal Tet as a critical factor that drives proper ISC maturation and maintains long-term adult epithelial homeostasis.

developmental biology↗

bioRxiv2026

MLL3/4 methyltransferases regulate the differentiation of pluripotent stem cells via cellular respiration

Enhancer-regulating epigenetic modifiers play critical roles in normal physiological processes and human pathogenesis. The major enhancer regulator paralogs MLL3 and MLL4 (MLL3/4) belong to the lysine methyltransferase 2 (KMT2) family, which catalyzes the methylation of lysine 4 on histone H3 (H3K4me). MLL3/4 are required for enhancer activation and are essential for mammalian development and stem cell differentiation. Although recent studies have linked MLL3/4 with different metabolic pathways in the regulation of stem cell self-renewal and cancer cell growth, the mechanisms connecting enhancer function to metabolic control remain elusive. Here, using respiration flux assays, stable isotope tracing, transcriptomics, and stem cell biology techniques, we show that the loss of MLL3/4 impairs glycolysis and mitochondrial respiration in murine embryonic stem cells. Mechanistically, MLL3/4 deficiency suppresses the expression of the rate-limiting glycolytic enzyme hexokinase 2 (HK2) and compromises the function of the oxoglutarate dehydrogenase (OGDH) complex, thereby coordinately impairing central carbon metabolism. Remarkably, combined restoration of HK2 and OGDH rescues the metabolic defects caused by MLL3/4 loss and reinstates differentiation capacity. Taken together, our study identifies a direct link between enhancer-regulating epigenetic machineries and metabolic control of cell fate transition, providing a mechanistic framework for understanding how enhancer malfunction contributes to developmental abnormalities and human diseases.

developmental biology↗

bioRxiv2022

Detergent-Free Decellularization Preserves the Structural and Biological Integrity of Murine Tendon

Tissue decellularization has demonstrated widespread applications across numerous organ systems for tissue engineering and regenerative medicine applications. Decellularized tissues are expected to retain structural and/or compositional features of the natural extracellular matrix (ECM), enabling investigation of biochemical factors and cell-ECM interactions that drive tissue homeostasis, healing, and disease. However, the dense collagenous tendon matrix has limited the efficacy of traditional decellularization strategies without the aid of harsh chemical detergents and/or physical agitation that disrupt tissue integrity and denature proteins involved in regulating cell behavior. Here, we adapted and established the advantages of a detergent-free decellularization method that relies on Latrunculin B actin destabilization, alternating hypertonic-hypotonic salt and water incubations, nuclease-assisted elimination of cellular material, and protease inhibitor supplementation under aseptic conditions. Compared with previous tendon decellularization studies, our method minimized collagen denaturation while adequately removing cells and preserving bulk tissue alignment and mechanical properties. Furthermore, we demonstrated that decellularized tendon ECM-derived coatings isolated from different mouse strains, injury states (i.e., naive and acutely injured/provisional), and anatomical sites harness distinct biochemical cues and robustly maintain tendon cell viability in vitro. Together, our work provides a simple and scalable decellularization method to facilitate mechanistic studies that will expand our fundamental understanding of tendon ECM and cell biology. Impact StatementIn this study, we present a decellularization method for tendon that does not rely on any detergents or physical processing techniques. We assessed the impact of detergent-free decellularization using tissue, cellular, and molecular level analyses and validated the preservation of tendon structural organization, collagen molecular integrity, and ECM-associated biological cues that are essential for studying physiological cell-ECM interactions. Lastly, we demonstrated the success of this method on healthy and injured tendon environments, across mouse strains, and for different types of tendons, illustrating the utility of this approach for isolating the contributions of biochemical cues within unique tendon ECM microenvironments.

bioengineering↗

bioRxiv2020

CellMAPtracer: A user-friendly tracking tool for long-term migratory and proliferating cells

Background Cell migration is a fundamental cell biological process of key importance in health and disease. Advances in imaging techniques have paved the way to monitor cells motility. An ever-growing collection of computational tools to track cells has improved our ability to analyze moving cells. However, few if any tools let the user supervise and correct cell tracks that are automatically detected. Thus, we developed CellMAPtracer, a tool to track cells in a semi-automated supervised fashion, thereby improving the accuracy and facilitating the long term tracking of migratory and dividing cells. CellMAPtracer is available with a user-friendly graphical user interface and does not require any coding or programming skills.Results We used CellMAPtracer to track fluorescently-labelled BT549 breast cancer cells. It allowed us to track dividing cells and determine the fate of the daughter cells with respect to migration speed or directionality and cell cycle length. Of note, we were able to track multi-daughter divisions, wherein a cell divides and gives rise to more than two cells. We also identified a not previously described speed change in the terminal phase of the cell cycle.Conclusion CellMAPtracer is a software tool for tracking cell migration and proliferation through a user-friendly interface that has a great potential to facilitate new discoveries in cell biology.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗

bioRxiv2020

Development of humanized mouse and rat models with full-thickness human skin and autologous immune cells

The human skin is a major barrier for host defense against many human pathogens, with several pathogens directly targeting the skin for replication and disease. The skin is also the primary route of infection for a myriad of vector-borne diseases; thus cutaneous immune cells play a major role in modulating transmission for such infectious diseases. Several human pathogens that target the skin as a major route of infection are unable to infect traditional rodent models or recapitulate the pathogenesis in humans. It is well established that differences exist in human skin and immune cell biology compared to rodent models. Therefore, rodent (mouse and rat) models that incorporate human skin and immune cells would addressed the above discussed technical gap, and enable in vivo mechanistic studies of human host-skin pathogen interactions, and support the development of novel therapeutics. Here, we introduce the novel human Skin and Immune System (hSIS)-humanized NOD-scid IL2Rgnull (NSG) mouse and Sprague-Dawley-Rag2tm2hera Il2rgtm1hera (SRG) rat models, co-engrafted with full-thickness human fetal skin, autologous fetal lymphoid tissues, and fetal liver-derived hematopoietic stem cells. hSIS-humanized rodents support the development of adult-like, full-thickness human skin and human lymphoid tissues, and support human immune cell development. Furthermore, the engrafted human skin supports Methicillin-resistant Staphylococcus aureus infection, demonstrating the utility of these humanized rodent models in studying human disease.

immunology↗

bioRxiv2020

Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

Parkinsons disease (PD) is a neurodegenerative disorder characterized by death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein -synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that -synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-{kappa}B signaling. Our study identifies a previously unknown function for -synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

neuroscience↗

bioRxiv2021

Visualizing multi-protein patterns at the synapse of neuronal tissue with DNA-assisted single-molecule localization microscopy

The development of super-resolution microscopy (SRM) has widened our understanding of biomolecular structure and function in biological materials. Imaging multiple targets within a single area would elucidate their spatial localization relative to the cell matrix and neighboring biomolecules, revealing multi-protein macromolecular structures and their functional co-dependencies. SRM methods are, however, limited to the number of suitable fluorophores that can be imaged during a single acquisition as well as the loss of antigens during antibody washing and restaining for organic dye multiplexing. We report the visualization of multiple protein targets within the pre- and postsynapse in 350-400 nm thick neuronal tissue sections using DNA-assisted single-molecule localization microscopy. Using antibodies labeled with short DNA oligonucleotides, multiple targets are visualized successively by sequential exchange of fluorophore-labeled complementary oligonucleotides present in the imaging buffer. The structural integrity of the tissue is maintained owing to only a single labelling step during sample preparation. Multiple targets are imaged using a single laser wavelength, minimizing chromatic aberration. This method proved robust for multi-target imaging in semi-thin tissue sections, paving the way towards structural cell biology with single-molecule super-resolution microscopy.

biophysics↗

bioRxiv2021

Light chain 2 is a Tctex-type related axonemal dynein light chain that regulates directional ciliary motility in Trypanosoma brucei

Flagellar motility is essential for the cell morphology, viability, and virulence of pathogenic kinetoplastids, including trypanosomes. Trypanosoma brucei flagella exhibit a bending wave that propagates from the flagellums tip to its base, rather than base-to-tip as in other eukaryotes. Thousands of dynein motor proteins coordinate their activity to drive ciliary bending wave propagation. Dynein- associated light and intermediate chains regulate the biophysical mechanisms of axonemal dynein. Tctex- type outer arm dynein light chain 2 (LC2) regulates flagellar bending wave propagation direction, amplitude, and frequency in Chlamydomonas reinhardtii. However, the role of Tctex-type light chains in regulating T. brucei motility is unknown. Here, we used a combination of bioinformatics, in-situ molecular tagging, and immunofluorescence microscopy to identify a Tctex-type light chain in the procyclic form of T. brucei (TbLC2). We knocked down TbLC2 expression using RNAi, rescued the knockdown with eGFP- tagged TbLC2, and quantified TbLC2s effects on trypanosome cell biology and biophysics. We found that TbLC2 knockdown resulted in kinetoplast mislocalization and the formation of multiple cell clusters in cell culture. We also found that TbLC2 knockdown reduced the directional persistence of trypanosome cell swimming, induced an asymmetric ciliary bending waveform, modulated the bias between the base-to- tip and tip-to-base beating modes, and increased the beating frequency. Together, our findings are consistent with a model of TbLC2 as a down-regulator of axonemal dynein activity that stabilizes the forward tip-to-base beating ciliary waveform characteristic of trypanosome cells. Our work sheds light on axonemal dynein regulation mechanisms that contribute to pathogenic kinetoplastids unique tip-to-base ciliary beating nature and how those mechanisms underlie dynein-driven ciliary motility more generally. Author SummaryKinetoplastea is a class of ciliated protists that include parasitic trypanosomes, which cause severe disease in people and livestock in tropical regions across the globe. All trypanosomes, including Trypanosoma brucei, require a cilium to provide propulsive force for directional swimming motility, host immune evasion, and various aspects of their cell cycle. Thus, a functional cilium is essential for the virulence of the parasite. Trypanosome cilia exhibit a unique tip-to-base beating mechanism, different from the base-to-tip beating of most other eukaryotic cilia. Multiple ciliary proteins are involved in the complex biophysical and biochemical mechanisms that underly the trypanosome ciliary beating. These include dynein motor proteins that power the beat, dynein-related light chains that regulate the beat, and many other proteins in the nexin-dynein regulatory complex, in the radial spokes, and associated with the central pair of microtubules, for example. Here, we identify a Tctex-type dynein light chain in T. brucei that we named TbLC2 because it has sequence homology, structural similarity, and ciliary localization like LC2 homologs in other organisms. We demonstrate that TbLC2 has critical dynein regulatory functions, with implications on the unique aspects of trypanosome ciliary beating and cellular swimming motility. Our study represents an additional step toward understanding the functions of the trypanosome ciliary proteome, which could provide novel therapeutic targets against the unique aspects of trypanosome ciliary motility.

biophysics↗

bioRxiv2025

Primitive steroidogenesis in mast cells: A novel regulatory mechanism for mast cell function

Mast cells, ancient immune sentinels, are crucial in immune responses, tissue homeostasis and inflammatory pathologies. This study unveils a previously unknown regulatory mechanism in mast cell biology: de novo steroidogenesis. Through comprehensive multi-omics analysis and functional assays, we demonstrate that mast cells express Cyp11a1 and produce pregnenolone, representing a primitive form of steroidogenesis. This cell-intrinsic steroidogenic pathway is essential for mast cell development, survival, and functional regulation. Genetic abrogation of mast cell steroidogenesis leads to exaggerated inflammatory and anaphylactic responses in vivo. Our integrative approach reveals extensive transcriptional and proteomic remodelling during mast cell regranulation, with steroidogenesis playing a pivotal role in coordinating recovery and tissue repair processes. We uncover significant sexual dimorphism in mast cell proteomes and a global uncoupling of transcriptional and translational programmes. These findings advance our understanding of mast cell physiology and provide a foundation for developing targeted therapies for mast cell-associated pathologies.

immunology↗