Biology subjects

van der Wel, N. N.

Publications and source records attributed to van der Wel, N. N..

4 recordsLinked to original sources

bioRxiv2026

Glutamine-driven mTORC1 activity enforces glycolytic bias, hyperactivation and aberrant proliferation in T cells in chronic B-cell leukemia

T-cell metabolic dysfunction is increasingly recognized as a hallmark of poor antitumor responses. Still, how distinct metabolic states shape T-cell function and which signaling pathways sustain them remains unclear. Here, we show that T cells from patients with chronic lymphocytic leukemia (CLL) adopt a hyperactivated phenotype characterized by high cytokine production, aberrant proliferation and a bias toward glycolysis, supported by sustained glutamine-driven mTORC1 activity. In parallel, T cells from these patients display alterations in mitochondrial network and cristae architecture, which further limit oxidative phosphorylation. mTORC1 inhibition reduces glucose dependence, restores mitochondrial metabolic engagement and normalizes T-cell activation and proliferation. Together, these findings identify metabolic disbalance as a central contributor to the hyperactivated state of T cells in CLL. We propose a model in which reduced OXPHOS reflects both mitochondrial defects that pre-exist in T cells from patients before TCR engagement, and a failure to engage mitochondrial metabolism upon activation supported by the actionable target mTORC1. HighlightsO_LIT cells from patients with chronic lymphocytic leukemia display high cytokine production and excessive division cycles upon CD3/28 engagement. C_LIO_LImTORC1-sustained glycolysis and defects in mitochondrial structure compromise OXPHOS in hyperactivated T cells. C_LIO_LIExogenous glutamine uptake sustains non-lysosomal mTORC1 activity in T cells. C_LI

immunology↗

bioRxiv2025

A conserved glycan motif overcomes antigenic variation inducing broadly reactive antibodies against the zoonotic pathogen Streptococcus suis

Streptococcus suis is a largely neglected but emerging bacterial zoonotic pathogen of global concern for animal welfare, antibiotic resistance development and human health. No effective vaccines are currently available. Here, we identified and characterized the function and structure of two cell wall polysaccharide variants in pathogenic S. suis strains using genetic deletion and (heterologous) complementation, lectin staining, glycan composition analysis and specialized NMR spectroscopy. Both glycan variants were anionic polymers that differed in the presence of glucose in the side-chain as a result of allelic variation in a glycosyltransferase gene. Deletion of this variable glycosyltransferase revealed an identical glycan core and affected S. suis morphology and lysozyme resistance. Immunization of pigs with this core domain induced antibodies recognizing a wide range of antigenically-diverse pathogenic S. suis strains. This study provides new insights for developing next-generation glycoconjugate vaccines, whereby a single-glycan target could protect against the emerging zoonotic pathogen S. suis.

microbiology↗

bioRxiv2025

Microtubule detyrosination alters nuclear mechanotransduction and leads to pro-hypertrophic signaling in hypertrophic cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and diastolic dysfunction and is accompanied by extensive cytoskeletal remodeling, including increased protein levels of desmin, tubulin and detyrosinated tubulin. We have previously demonstrated that tubulin detyrosination contributes to diastolic dysfunction. Microtubules are connected to the nucleus by the LINC complex, yet the role of cytoskeleton-nucleus interactions in HCM remain poorly understood. ObjectivesWe investigated whether cytoskeletal remodeling in HCM alters nuclear morphology and mechanics, and modulates hypertrophy-associated signaling pathways. MethodsNuclear morphology was assessed by electron microscopy and immunofluorescence in cardiac septal tissue from obstructive HCM patients (N=19) and non-failing donors (NF, N=8), as well as in Wild-Type (WT, N=18) and homozygous HCM-associated Mybpc3 c.2373InsG mice (Mybpc3c.2373InsG, N=19). A novel live-cell imaging approach was used to study nuclear deformation during cardiomyocyte contraction. YAP1 nuclear translocation was measured to evaluate downstream mechanosensitive signaling and detyrosination inhibitor epoY was used to test causality. ResultsNuclei were highly invaginated and enlarged in HCM in both patients and mice. Nuclear deformation during contraction was restricted in HCM cardiomyocytes, indicating altered mechanotransduction. These changes were associated with increased YAP1 nuclear localization and induction of YAP1 target and hypertrophic genes. Inhibition of microtubule detyrosination reduced nuclear invaginations, restored nuclear deformation and decreased YAP1 nuclear translocation. ConclusionCytoskeletal remodeling in HCM is associated with altered nuclear morphology and mechanotransduction, accompanied by YAP1 translocation which may contribute to hypertrophic remodeling. Targeting microtubule detyrosination rescues this phenotype, identifying nuclear mechanotransduction as a potential therapeutic target for HCM. Unstructured abstractHypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and diastolic dysfunction and is accompanied by extensive cytoskeletal remodeling, including increased desmin, tubulin, and detyrosinated tubulin levels, which we previously showed contribute to impaired relaxation. Since microtubules connect to the nucleus via the LINC complex, we investigated whether cytoskeletal remodeling alters nuclear morphology, mechanics, and hypertrophy-associated signaling. Using electron microscopy and immunofluorescence in cardiac septal tissue from obstructive HCM patients and non-failing donors, and immunofluorescence and live-cell imaging in septal tissue from Wild-Type and homozygous HCM-associated Mybpc3 c.2373InsG mice, we found that nuclei were enlarged and highly invaginated, with restricted nuclear deformation during contraction, indicating altered mechanotransduction. These changes were associated with increased YAP1 nuclear localization and increased expression of YAP1 target and hypertrophic genes. Inhibiting microtubule detyrosination reduced nuclear abnormalities, restored nuclear deformation, and decreased YAP1 nuclear translocation, identifying nuclear mechanotransduction as a potential therapeutic target in HCM. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/646061v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@7f915forg.highwire.dtl.DTLVardef@12131c6org.highwire.dtl.DTLVardef@4aff5eorg.highwire.dtl.DTLVardef@1c3a3a8_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICytoskeletal remodeling contributes to nuclear abnormalities and impaired mechanotransduction in hypertrophic cardiomyopathy. C_LIO_LIMicrotubule detyrosination promotes nuclear invaginations and increased YAP1 signaling in hypertrophic cardiomyopathy. C_LIO_LIPharmacological reduction of detyrosinated tubulin normalizes nuclear structure and mechanosignaling. C_LIO_LITargeting nuclear-cytoskeletal coupling may provide new therapeutic strategies for hypertrophic cardiomyopathy. C_LI

physiology↗

bioRxiv2021

Lipid and nucleocapsid N-protein accumulation in COVID-19 patient lung and infected cells

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global outbreak and prompted an enormous research effort. Still, the subcellular localization of the corona virus in lungs of COVID-19 patients is not well understood. Here, the localization of the SARS-CoV-2 proteins is studied in postmortem lung material of COVID-19 patients and in SARS- CoV-2 infected Vero cells, processed identically. Correlative light and electron microscopy on semi- thick cryo-sections, demonstrated induction of electron-lucent, lipid filled compartments after SARS- CoV-2 infection in both lung and cell cultures. In lung tissue, the non-structural protein 4 and the stable nucleocapsid N-protein, were detected on these novel lipid filled compartments. The induction of such lipid filled compartments and the localization of the viral proteins in lung of patients with fatal COVID-19, may explain the extensive inflammatory response and provide a new hallmark for SARS- Cov-2 infection at the final, fatal stage of infection.

microbiology↗