Biology subjects

Bosc, C.

Publications and source records attributed to Bosc, C..

9 recordsLinked to original sources

bioRxiv2026

VASH1 phosphorylation regulates tubulin detyrosination via CNP/PRKG1α signaling in DRG neurons.

Functional neuronal circuit formation requires precise regulation of axon growth and branching through dynamic cytoskeletal remodeling. Although microtubule detyrosination/re-tyrosination critically controls microtubule dynamics, how extracellular signals regulate this process remains unclear. Here, we identify a direct link between C-type natriuretic peptide, protein kinase cGMP-dependent 1 (CNP/cGMP/PRKG1) signaling and microtubule detyrosination in dorsal root ganglion (DRG) neurons. CNP stimulation induces growth cone enlargement, increases tyrosinated tubulin within growth cones, and reduces detyrosinated tubulin along axons, effects abolished by PRKG1 inhibition. Pharmacological inhibition or genetic deletion of the detyrosinating enzyme VASH1 phenocopies CNP-induced growth cone remodeling. In vitro kinase assays identify VASH1 as a direct PRKG1 substrate and reveal a specific C-terminal serine phosphorylation site (serine 337) that suppresses VASH1-SVBP microtubule association and detyrosination activity. Together, these findings establish VASH1-SVBP as a key downstream effector linking extracellular guidance signaling to microtubule remodeling during DRG neuronal development.

cell biology↗

bioRxiv2026

Uncovering aquatic toxicity as a specific stressor among multiple environmental drivers affecting the functional structure of French stream macroinvertebrate communities

O_LISince recent years, freshwater ecosystems such as rivers are subjected to increasing pressures from human-induced drivers of changes, including chemical contamination, warming and nutrient enrichment. Among those, toxic chemicals are particularly concerning, as aquatic contamination is strongly increasing but their effects on ecosystem structure and functioning remain poorly understood and difficult to predict. Yet, those are expected to impact freshwater ecological communities, notably through selecting species exhibiting particular biological traits. A growing literature tested predictions on the effects of multiple environmental drivers, including chemicals, on the functional structure of macroinvertebrate communities, but disentangling the respective influences of the different drivers on the observed patterns usually remains challenging. C_LIO_LIHere, we used multivariate analyses with variation partitioning to estimate the independent and combined effects of toxic contamination, water temperature and nutrient load on the species abundances and biological traits of macroinvertebrate communities in 76 French streams. Toxic contamination was quantified based on the Gammarus feeding inhibition indicator recorded during repeated in situ biotests. We then compared trait responses with expectations from a priori predictions derived from the literature, and looked at the link between taxon turnover and taxonomic and functional diversity metrics using linear models. C_LIO_LIOur results suggest that, when considered independently, each driver had specific impact on invertebrate taxa and biological traits, with different consequences on community composition and diversity. Notably, we showed significant changes in taxonomic composition linked to toxicity, associated with the reduction of both taxonomical and functional richness, but no significant effect on biological trait composition. In contrast, temperature and moreover nutrient load strongly effected traits, but with variables associations with diversity metrics depending on driver. Finally, when all three drivers were considered in combination, patterns were similar to those observed for temperature, suggesting dominance rather than additive effects between drivers. C_LIO_LIOur study reveals particular negative impacts of toxicity on macroinvertebrate communities in contrast with other drivers, which highlights the potential risk posed by contaminants for freshwater biodiversity. C_LI

ecology↗

bioRxiv2025

Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer, yet our ability to map these connections systematically remains limited. Individual gene-gene interaction studies have provided insights1,2, but they miss the emergent properties of pathways working together. To address this challenge, we developed a multi-gene approach to pathway mapping and applied it to CRISPR data from the Cancer Dependency Map3. Our analysis of the electron transport chain revealed certain blood cancers, including acute myeloid leukemia (AML), depend on an unexpected link between Complex II and purine metabolism. Through stable isotope metabolomic tracing, we found that Complex II directly supports de novo purine biosynthesis and exogenous purines rescue AML from Complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that Complex II must oxidize to sustain purine synthesis. This connection translated to a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML to Complex II inhibition. In mouse models, targeting Complex II triggered rapid disease regression and extended survival in aggressive AML. The clinical relevance of this pathway emerged in human studies, where higher Complex II gene expression correlates with both resistance to mitochondria-targeted therapies and worse survival outcomes specifically in AML patients. These findings establish Complex II as a central regulator of de novo purine biosynthesis and identify it as a promising therapeutic target in AML.

cancer biology↗

bioRxiv2025

The Mn-motif protein MAP6d1 assembles ciliary doublet microtubules

Most eukaryotic cells have cilia that serve vital functions in sensing, signaling, motility. The core architecture of cilia is an array of microtubule doublets, which consist of a complete A-tubule and an incomplete B-tubule. The mechanisms governing the assembly of this complex structure remain poorly understood. Here, using total internal reflection fluorescence microscopy and cryo-electron tomography, we investigate the role of MAP6d1, a brain-specific protein containing microtubule lumen-targeting Mn-motifs. We show that MAP6d1 assembles stable microtubule doublets by recruiting tubulin dimers onto the lattice of the A-tubule to initiate the nucleation of the B-tubule. MAP6d1 also promotes the formation of luminal protofilaments in singlet and doublet microtubules, a previously undescribed phenomenon that likely enhances microtubule stability. In neurons, MAP6d1 localises to the proximal part of primary cilia via its Mn-motif, with its loss resulting in shortened cilia, a characteristic of ciliopathies. MAP6d1 is thus the first microtubule-associated protein found to assemble microtubule doublets, uncovering new functions for Mn-motif proteins in neurons.

cell biology↗

bioRxiv2023

FAO-supported OxPhos leukemic stem cells are sensitive to cold.

Targeting mitochondrial oxidative phosphorylation (OxPhos) metabolism has revealed a potential weakness for leukemic stem cells (LSCs) that can be exploited for therapeutic purposes. Fatty acids oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some AML and for chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4{degrees}C (cold killing challenge: CKC4), as a novel vulnerability that selectively kills FAO-supported OxPhos LSCs in Acute Myeloid Leukemia while sparing normal hematopoietic stem cells (HSCs). Cell death of OxPhos leukemic cells was induced by membrane permeabilization at 4{degrees}C while by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells into OxPhos metabolism sensitized them to CKC4. We show using lipidomic and proteomic analyzes that OxPhos shapes the composition of the plasma membrane and introduce variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Cold sensitivity is a potential OxPhos biomarker. SignificanceThis study reveals that mitochondrial energetics fueled by FAO metabolism introduces membrane fragility upon cold exposure in OxPhos-driven AMLs and in LSCs. This novel physical property of Leukemic cells and LSCs opens new avenues for biomarker and diagnostics as well as for anti-OxPhos drug screening and LSCs targeting. One Sentence SummaryOxPhos leukemic cells die at 4{degrees}C

cancer biology↗

bioRxiv2022

VASH1-SVBP and VASH2-SVBP generate different detyrosination profiles on microtubules

The detyrosination/tyrosination cycle of -tubulin is critical for proper cell functioning. VASH1-SVBP and VASH2-SVBP are ubiquitous enzyme complexes involved in microtubule detyrosination. However, little is known about their mode of action. Here, we show in reconstituted systems and in cells that VASH1-SVBP and VASH2-SVBP drive global and local detyrosination of microtubules, respectively. We solved the cryo-electron microscopy structure of human VASH2-SVBP bound to microtubules, revealing a different microtubule-binding configuration of its central catalytic region compared to VASH1-SVBP. We further show that the divergent mode of detyrosination between the two enzymes is correlated with the microtubule-binding properties of their disordered N- and C-terminal regions. Specifically, the N-terminal region is responsible for a significantly longer residence time of VASH2-SVBP on microtubules compared to VASH1-SVBP. We suggest that this VASH domain is critical for microtubule-detachment and diffusion of VASH-SVBP enzymes on the lattice. Together, our results suggest a mechanism by which these enzymes could generate distinct microtubule subpopulations and confined areas of detyrosinated lattices to drive various microtubule-based cellular functions. SUMMARYVASH1-SVBP and VASH2-SVBP produce global and local detyrosination patterns of microtubule lattices, respectively. These activities rely on the interplay between the N- and C-terminal disordered regions of the enzymes, which determine their differential molecular mechanism of action. GRAPHICAL ABSTRACTSchematic representation of divergent molecular mechanisms of action of VASH-SVBP detyrosination complexes.

cell biology↗

bioRxiv2021

Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer's disease

In neurons, dynamic microtubules play regulatory roles in neurotransmission and synaptic plasticity. While stable microtubules contain detyrosinated tubulin, dynamic microtubules are composed of tyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination (Tyr/deTyr) cycle modulates microtubule dynamics and synaptic function. In the Tyr/deTyr cycle, the C-terminal tyrosine of -tubulin is re-added by tubulin-tyrosine-ligase (TTL). Here we show that TTL+/- mice exhibit decreased tyrosinated microtubules, synaptic plasticity and memory deficits, and that reduced TTL expression is a feature of sporadic and familial Alzheimers disease (AD), with human APPV717I neurons having less dynamic microtubules. We find that spines visited by dynamic microtubules are more resistant to Amyloid{beta}1-42 and that TTL, by promoting microtubule entry into spines, prevents A{beta}1-42-induced spine pruning. Our results demonstrate that the Tyr/deTyr cycle regulates synaptic plasticity, is protective against spine injury, and that tubulin re-tyrosination is lost in AD, providing evidence that a defective Tyr/deTyr cycle may contribute to neurodegeneration.

neuroscience↗

bioRxiv2020

Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

Drug tolerant leukemic cell subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these Relapse-Initiating Cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncovered that the G-protein coupled receptor CALCRL is expressed in leukemic stem cells (LSCs) and RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM) and not CGRP correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency and sensitizes to cytarabine in patient-derived xenograft (PDX) models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.

cancer biology↗

bioRxiv2020

Mitochondrial determinants of response and resistance to venetoclax plus cytarabine duplet therapy in acute myeloid leukemia

The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen.

cancer biology↗