Biology subjects

Jaattela, M.

Publications and source records attributed to Jaattela, M..

6 recordsLinked to original sources

bioRxiv2026

Extracellular vesicles from antigen-activated B cells stimulate oncogenic herpesvirus lytic gene expression

B cell-derived extracellular vesicles (B-EVs) have been associated with immunomodulatory functions like antigen presentation, cytokine signaling, and T cell activation. However, little is known about the general composition of B-EVs or how the state of the donor cells affects the B-EV composition or functions. We performed integrated proteomic, lipidomic, and transcriptomic analyses of EVs secreted by B cells in resting conditions or upon 30 min of B cell receptor (BCR) activation. Antigen-driven BCR stimulation led to acute remodeling of the protein and lipid composition, and RNA cargo of the B-EVs, which also translated into differential responses in recipient B cells. Remarkably, EVs from activated B cells stimulated lytic gene expression of latent oncogenic {gamma}-herpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). These findings suggest a novel mechanism for the potentially oncogenic reactivation of these lifelong-persisting latent herpesviruses, residing in B cells. Our results support a mechanism in which, upon immune activation, B-EVs from antigen-specific B cells induce viral reactivation in bystander B cells in a paracrine manner, providing molecular insights that bridge immune activation and the pathogenesis of {gamma}-herpesvirus infections.

immunology↗

bioRxiv2025

Lipid Landscape of human cells

Eukaryotic cells synthesise thousands of lipid species, yet the principles that organise them across compartments remain unclear. Here we introduce PAP-SL, parallel (immuno)affinity purification coupled to shotgun lipidomics, to map [~]300 lipid species across six compartments of human cells and uncover general rules of lipid organisation. Correlation analyses of stoichiometric lipid compositions resolved archetypal distribution trajectories. Biosynthetic origin set the baseline: mitochondrial and lysosomal pathways generated confined pools, whereas the ER acted as a dispatch hub shaping downstream membrane territories. The ER established the saturated plasma membrane through transfer of phosphatidylserine, sphingolipids, and cholesterol, together with species-level selection of more saturated glycerophospholipids across diverse headgroups, while less-saturated species moved unselectively into mitochondria. The ER also channelled ether-linked glycerophospholipids to lysosomes, forming a territory dominated by ether phosphatidylcholine that collapsed under ethanolamine-driven metabolic rewiring. PAP-SL defines a framework to resolve lipid organisation and its metabolic plasticity in health and disease.

systems biology↗

bioRxiv2025

Role of N-glycosylation as a determinant of ATG9A conformations and activity

In this study we investigate the effects of glycosylation at position N99 on the structural dynamics and lipid scrambling activity of ATG9A, a key autophagy protein, using microsecond all-atom molecular dynamics (MD) simulations. ATG9A is an integral membrane protein involved in autophagosome biogenesis, and glycosylation at N99 is known to play a critical, yet poorly understood role in its function. The MD simulations revealed that the hydrophilic central cavity of ATG9A supports lipid reorientation and partial transbilayer movements, consistent with its lipid scrambling activity observed experimentally. N-glycosylation at N99 was found to enhance cooperative interactions between protomers, facilitating lipid insertion and traversal within the central cavity. These findings align with the proposed mechanism of ATG9A role in lipid redistribution across the phagophore membrane during autophagy. However, mutagenesis experiments that abolish N-glycosylation in ATG9A (ATG9AN99A and ATG9AN99D mutants) did not show a significant change in autophagy flux, suggesting that further experimental approaches, such as lipid scramblase assays, are needed to pinpoint the function of glycosylation. In this study we also observed an asymmetric protomer conformations in ATG9A, contrasting with symmetric structures obtained from cryo-EM, suggesting that the structural heterogeneity of the protein could be further explored in cryo-EM datasets. Overall, the study highlights the importance of incorporating glycosylation in computational studies of membrane proteins and offers valuable insights into the molecular mechanisms of lipid transport in autophagy, with potential implications for other lipid scramblases and flippases.

biophysics↗

bioRxiv2024

TMEM165 replenishes lysosomal calcium stores, protects cells against calcium overload, and mediates calcium-induced lysosomal H+ leakage

The proper function of lysosomes depends on their ability to store and release calcium. While several lysosomal calcium release channels have been described, how mammalian lysosomes replenish their calcium stores has not been determined. Using genetic depletion and overexpression techniques combined with electrophysiology and visualization of subcellular ion concentrations and their fluxes across the lysosomal membrane, we show here that TMEM165 imports calcium to the lysosomal lumen and mediates calcium-induced lysosomal proton leakage. Accordingly, TMEM165 accelerates the recovery of cells from cytosolic calcium overload thereby enhancing cell survival while causing a significant acidification of the perilysosomal area and the entire cytosol. These data indicate that in addition to its essential role in the glycosylation in the Golgi, a small but significant fraction of TMEM165 localizes on the lysosomal limiting membrane, where it protects cells against cytosolic calcium overload, preserves lysosomal function by refilling lysosomal calcium stores and regulates perilysosomal and lysosomal pH.

cell biology↗

bioRxiv2023

Acidic Sphingomyelinase Interactions with Lysosomal Membranes and Cation Amphiphilic Drugs: a Molecular Dynamics Investigation

Lysosomes are pivotal in cellular functions and disease, influencing cancer progression and therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) are known as ASM inhibitors and have anti-cancer activity, but the structural mechanisms of their interactions with the lysosomal membrane and ASM are poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into the interaction of glycosylated ASM with the lysosomal membrane and the effects of one of the CAD representatives, i.e., ebastine on the membrane and ASM. Our results confirm the ASM association to the membrane through the saposin domain, previously only showed with coarse grained models. Furthermore, we elucidated the role of specific residues and ASM-induced membrane curvature in lipid recruitment and orientation. Ebastine also interferes with the association of ASM with the membrane at the level of a loop in the catalytic domain engaging in membrane interactions. Our computational approach, applicable to various CADs or membrane compositions, provides insights into ASM and CAD interaction with the membrane, offering a valuable tool for future studies.

bioinformatics↗

bioRxiv2020

Conditioned media from MCF7 and BT474 breast cancer cells induce insulin resistance in skeletal muscle myotubes

BackgroundMetabolic disorders are prevalent in women with breast cancer, increasing mortality and cancer recurrence rates. Despite clinical implications, the cause of breast cancer-associated metabolic dysfunction remains poorly understood. Skeletal muscle is crucial for insulin-stimulated glucose uptake, thus key to whole-body glucose homeostasis. In this study, we determined the effect of breast cancer cell-conditioned media on skeletal muscle glucose uptake in response to insulin. MethodL6 myotubes overexpressing myc-tagged GLUT4 (GLUT4myc-L6) were incubated with 40% conditioned media from tumorigenic MCF7 or BT474, or non-tumorigenic control MCF10A breast cells. Mass-spectrometry-based proteomics was applied to detect molecular rewiring in response to breast cancer in the muscle. Expression of myogenesis and inflammation markers, GLUT4 translocation, [3H]-2-deoxyglucose (2DG) uptake, and intramyocellular insulin signalling were determined. ResultsBreast cancer cell-conditioned media induced proteomic changes in pathways related to sarcomere organisation, actin filament binding, and vesicle trafficking, disrupted myogenic differentiation, activated an inflammatory response via NF-{kappa}B, and induced muscle atrophy. Basal and insulin-stimulated GLUT4 translocation and 2DG uptake were reduced in myotubes treated with breast cancer cell-conditioned media compared to the control. Insulin signalling via the Rho GTPase Rac1 was blocked in breast cancer-treated myotubes, while Akt-TBC1D4 signalling was unaffected. ConclusionConditioned media from MCF7 and BT474 breast cancer cells reduced skeletal muscle glucose uptake via inhibition of GLUT4 translocation and intramyocellular insulin signalling by selectively blocking Rac1 activation and inducing inflammation. These findings indicate that the rewiring of skeletal muscle proteome, inflammation, and insulin signalling could play a role in metabolic dysfunction in patients with breast cancer.

cancer biology↗