Biology subjects

Vicente-Manzanares, M.

Publications and source records attributed to Vicente-Manzanares, M..

3 recordsLinked to original sources

bioRxiv2026

Molecular Analysis and Computational Modeling Reveal Temporally Separable Responses triggered by DENV-Induced Soluble Factors in Endothelial Cells

Dengue virus (DENV) represents a growing global health challenge with billions of people at risk. Severe Dengue (SD), a complication of DENV infection that involves generalized hemorrhage, is driven, at least in part, by endothelial dysfunction. Endothelial dysfunction refers to increased permeability due to inflammation, mechanical injury and/or modification of the genetic program of endothelial cells. Previous work showed that exposure of endothelial cells to conditioned media from DENV-infected cells (CMDV) increased permeability and cellular stiffness, repressed endothelial markers and induced mesenchymal genes. However, the generality, extent, mechanism and ultimate impact of these events in the onset of SD remain elusive. Here, we integrate analysis from in vitro infection of endothelial cells with computational modeling to investigate the key features of CMDV-induced endothelial alterations and their potential impact on endothelial dysfunction. We found that CMDV increased SNA1 and CDH2 expression, while suppressing endothelial genes OCLN and CDH5. Global transcriptomics analysis revealed that CMDV triggered a transient pro-inflammatory response, followed by induction of selected tissue repair genes and matrix remodeling. A non-directed asynchronous network model (NDAM-CMDV) identified IL6 and FN1 as central nodes of DENV-induced endothelial trans-differentiation, providing new molecular insights that predict the evolution of the disease and identify potential therapeutic targets.

cell biology↗

bioRxiv2025

Paclitaxel induces NM2-dependent cellular contraction independent of microtubule acetylation in live cells

In this study, we have investigated the crosstalk between microtubule dynamics and actomyosin contractility in cancer cells treated with taxanes, which are chemotherapeutic agents used to treat solid tumors. We found that paclitaxel (PTXL) induced cell contraction through a mechanism that involved the rapid dissociation of GEF-H1 from microtubules, and the phosphorylation and acute activation of NM2 in a RhoA-dependent manner. Mutation of the major -tubulin acetylation site, K40R, markedly slowed and reduced the efficiency of PTXL-induced GEF-H1 dissociation, indicating that K40 acetylation is required for the full, rapid release of GEF-H1 from the microtubule lattice. These findings were corroborated using inhibitors of tubulin deacetylase HDAC6, which promoted a slow release of GEF-H1 from microtubules and a lagged accumulation of phosphorylated NM2. Unexpectedly, depletion of tubulin acetyltransferase TAT1 also induced NM2 phosphorylation, indicating that microtubule acetylation is involved in the maintenance of contractile homeostasis. Together, these results indicate that PTXL induces rapid cellular contraction dependent on the GEF-H1-RhoA-ROCK axis, in which K40 acetylation of -tubulin gates the efficiency of GEF-H1 dissociation from microtubules, whereas homeostatic microtubule acetylation maintains appropriate levels of cellular contractility through long-term control of NM2 phosphorylation and actomyosin organization.

cell biology↗

bioRxiv2025

Molecular Control of Non-Muscle Myosin II-A Aggregation and Intracellular Dynamics by motor- or tail-specific MYH9 Mutations

Mutations in the MYH9 gene, which encodes the actin-based molecular motor non-muscle myosin II-A (NM2-A), cause a group of blood disorders termed MYH9-related diseases (MYH9-RD). While correlation between genotype and phenotype is not well characterized at a molecular level, motor mutations seem to cause more severe phenotypes than tail mutations. Motor domain mutation N93K, previously described as activity-impairing, causes in fact an almost non-significant defect on motor function in vitro. Conversely, it increases NM2-A filament stability and interaction with the myosin chaperone UNC45a in stress fiber-forming cells. This also alters its subcellular localization and effect on adhesion dynamics. Similar cellular effects are observed in cells expressing NM2-A E1841K, a prototypical tail mutation. In cells devoid of stress fibers such as megakaryocytes, NM2-A N93K forms large, amorphous, concentration-dependent aggregates that also contain wild type NM2-A and UNC45a. Conversely, NM2-A E1841K forms concentration-independent aggregates that exclude wild type NM2-A and UNC45a. Our data shows that the N93K mutation reduces the fraction of functional cellular NM2-A by enhancing the stability of NM2-A filaments and/or promoting protein aggregation together with wild type NM2-A. Conversely, NM2-A E1841K form aggregates that do not affect wild type NM2-A. These observations are consistent with the molecular severity observed in primary cells from patients of these genotypes.

cell biology↗