Biology subjects

Reisacher, C.

Publications and source records attributed to Reisacher, C..

4 recordsLinked to original sources

bioRxiv2026

CBX3 Deletion Overcomes Ferroptosis Resistance in Colorectal Cancer by Targeting IFNγ/SLC7A11/SLC3A2 Axis

System Xc- (SLC7A11/SLC3A2) maintains redox balance by supporting glutathione synthesis, thereby preventing lipid peroxidation and ferroptosis, and represents a promising therapeutic target in cancer. In this work, we revealed that an important epigenetic regulator, CBX3 deletion significantly increased intracellular ROS and lipid ROS level following ferroptosis inducing, particularly under IFN{gamma} stimulation, thereby sensitized CRC cells to ferroptosis in vitro using human CRC cells as well as in vivo using MC38 syngenetic tumors. RNAseq with mice syngeneic tumors revealed an 11-gene oxidative stress signature downregulated in Cbx3KO tumors after combined treatment; its low expression score correlated with improved overall survival in CRC patients. Among them, Slc7a11, Ptgs2, and Cth were identified as CBX3 direct target genes. Additionally, several amino acid transporters functionally coupled to Xc- antiporter, as Slc3a2, Slc7a5, Slc1a5 and Slc6a9, all significantly decreased in Cbx3KO tumor under RSL3+IFN{gamma} treatment. Mechanistically, CBX3 binds directly to the promoter of Slc7a11 or Slc3a2 to sustain their expression and redox balance to resist ferroptosis in CRC. Knockout of CBX3 in CRC cells significantly impaired RNA polymerase II recruitment to the promoter of SLC7A11 or SLC3A2 and reduced SLC7A11 and SLC3A2 expression, an effect that was further exacerbated under IFN{gamma} stimulation but restored by STAT1 deletion. Overall, CBX3 protects CRC from oxidative stress by maintaining the functional integrity of IFN{gamma}/STAT1/SLC7A11/SLC3A2 axis, positioning CBX3 as a potential therapeutic target for enhancing ferroptosis therapies in CRC.

cancer biology↗

bioRxiv2026

Progerin disrupts intestinal epithelial homeostasis by impairing mitochondrial metabolism and absorptive enterocyte maturation

Hutchinson-Gilford progeria syndrome (HGPS) is a segmental premature ageing disease that predominantly affects tissues with high regenerative capacity. Although the intestine is the most rapidly self-renewing tissue of adult mammals, it has so far been considered only as a source of microbiota-derived disturbances in progeria, and whether the intestinal epithelium is itself a target of progerin remains unknown. Here, using the LmnaG609G/G609G and LmnaG609G/+ mouse models, intestinal organoids and single-cell RNA sequencing, we show that progerin is expressed in colonic enterocytes and in SMA+ subepithelial myofibroblasts of the stem-cell niche. Heterozygous progeria mice develop increased intestinal permeability from 30 weeks of age, reaching levels reported in physiologically aged (>20-month-old) mice. Progeria-derived intestinal organoids display reduced mitochondrial oxygen consumption, a compensatory increase in glycolysis and impaired crypt budding. Single-cell transcriptomics of the colonic epithelium and lamina propria revealed that, while lineage composition is preserved, progerin induces a coordinated reprogramming characterised by repression of oxidative phosphorylation and mitochondrial quality-control genes, including Nod2, activation of interferon, TNF-NF-kB and innate defence programs, and up-regulation of RNA-processing and chromatin-associated pathways. Trajectory analysis showed that progeria absorptive enterocytes selectively fail to reach terminal differentiation states and retain progenitor-like WNT, NOTCH and EGFR signatures, while lacking the mitochondrial programs required for maturation. Together, these findings identify the intestinal epithelium as a cell-intrinsic target of progerin and support a model in which mitochondrial insufficiency stalls absorptive enterocyte maturation and weakens the intestinal barrier, recapitulating, prematurely, key features of colon ageing.

pathology↗

bioRxiv2025

The VapBC Toxin Antitoxin System Enhances Shigella flexneri Fitness Through Coordination of Metabolic Stress Adaptation and Virulence

Shigella flexneri is a facultative intracellular pathogen that causes bacillary dysentery by invading and replicating within intestinal epithelial cells. Successful intracellular survival requires the bacterium to balance metabolic adaptation with the sustained expression of virulence programs by the type III secretion system (T3SS). Toxin- antitoxin (TA) systems, including the highly conserved type II VapBC module, are classically associated with plasmid maintenance via post-segregational killing, but their broader roles during infection remain poorly understood. Here, we investigate the function of the VapBC system during S. flexneri infection. We show that the vapBC operon is activated in response to intracellular stress and that VapC-dependent cleavage of initiator tRNAfMet occurs specifically during infection. The stringent response, primarily mediated by SpoT, appears to influence operon responsiveness by maintaining vapB expression levels, while iron limitation emerges as a strong activator of vapC transcription and activity. Deletion of vapBC impairs T3SS activation and bacterial dissemination, despite normal invasion, and induces a strong host interferon response, including the upregulation of guanylate-binding proteins (GBPs), known to restrict bacterial spread. Transcriptomic profiling of the{Delta} vapBC mutant reveals downregulation of core metabolic genes and upregulation of envelope stress and other TA modules, indicating a loss of intracellular homeostasis. These findings uncover a novel role for VapBC in promoting Shigella fitness by coordinating stress adaptation, virulence expression, and immune evasion, thereby sustaining the bacteriums intracellular lifestyle.

microbiology↗

bioRxiv2022

The human-specific miR-6762-5p is an activator of RhoA GTPase enhancing Shigella flexneri intercellular spreading

MicroRNAs have recently emerged as major players in host-bacterial pathogens interaction, either as part of the host defense mechanism to neutralize infection or as a bacterial arsenal aimed at subverting host cell functions. Here we identify the newly evolutionary emerged human microRNA miR-6762-5p as a new player in the host-Shigella interplay. A microarray analysis in infected epithelial cells allowed the detection of this miRNA exclusively during the late phase of infection. Conditional expression of miR-6762-5p combined with a transcriptome analysis indicated a role in cytoskeleton remodeling. Likewise, miR-6762-5p enhanced stress fibers formation through RhoA activation and in silico analysis identified several regulators of RhoA activity as potential direct transcriptional targets. We further showed that miR-6762-5p expression induces an increase in Shigella intercellular spreading, while miR-6762-5p inhibition reduced bacterial dissemination. Overall, we have identified a human-specific miR-6762-5p acting specifically at the Shigella dissemination step. We propose a model in which the expression of miR-6762-5p induces cytoskeleton modifications through RhoA activation to achieve a successful dissemination of Shigella in the host.

microbiology↗