Biology subjects

Rogalska, M.

Publications and source records attributed to Rogalska, M..

3 recordsLinked to original sources

bioRxiv2024

On the mode of anti-C. albicans activity of a bis(benzoxaborole) analogue of Tavaborole

We presented the pharmacodynamic relationship between benzoxaborole concentrations and Candida albians blastoconidial population dynamics. Bis(benzoxaborole) analogue (2) and Tavaborole (ref.) showed comparable moderate effects against C. albicans (time-kill kinetic assays). Benzoxaboroles inhibited the C. albicans growth during 72 h (fungicidal after 2 h of that time) with metabolic reduction (%R=64). Biofilm-inhibiting concentration (BIC50=2 g/mL) is the lowest concentration of bezoxaboroles that presented 50% inhibition of biofilm metabolic activity vs non-treated control. 2 displayed poor ability to inhibit morphogenesis of C. albicans. Safety and fungicidal activity are still in high demand against biofilm grown on fibroblasts and the zebrafish model in vivo. This biofilm model was used to study the interactions between the C. albicans morphogenesis and benzoxaboroles. Benzoxaboroles displayed selectivity in cytotoxic effects. 2 exhibited significantly lower embryotoxicity vs ref. IC50>128 g/mL for 2. Ref. at 256 g/mL showed approximately 80% viability of VERO E6 cells. A higher selectivity of the ref--drug to the pathogen than to the mammalian cells was observed. Contrariwise, ref. and 2 showed IC50=2 g/mL against PBMCs. Benzoxaborole antifungal development targets ergosterol binding. RNAseq data indicated that efflux pumps (MDR) in C. albicans were upregulated. Inositol-1-phosphate synthase was repressed under the benzoxaborole treatment. MDR1 upregulation by 2 was accompanied by the IFD6 (aldo-keto reductase) increase and the coordination of multiple coactivators (IFD6, TNA1 encoding putative nicotinic acid transporter). Benzoxaboroles represent a similar resistance mechanism to azoles due to the subsequent expression of MDR1 and IDF6. Docking studies confirmed the proposed interactions of benzoxaborole adenosinemonophosphate adduct with LeuRS. Moreover, C5_04480C_A (cell wall biogenesis, protein folding, modification, and destination) was negatively regulated in response to the benzoxaborole stress. Benzoxaborole-altering efflux inhibitors are important for the development of combination strategies in candidiasis. Our findings present an innovative concept that can inspire further studies for designing and building new antifungal benzoxaborole. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/605614v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@10d0037org.highwire.dtl.DTLVardef@894266org.highwire.dtl.DTLVardef@1663f05org.highwire.dtl.DTLVardef@1b3736b_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Communication between the nucleus and the mitochondria via NDUFS4 alternative splicing in gastric cancer cells

A constant communication between the nucleus and the mitochondria allows both organelles to ensure cellular homeostasis and adaptation to mitochondrial stress. Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving a large number of nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct subsets of genes in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic analyses and RNA-seq profiles of IQGAP1KO and parental cells show that IQGAP1KO alters a specific AS event of the mitochondrial respiratory chain complex I subunit NDUFS4 and downregulates a subset of complex I subunits. In IQGAP1KO cells, respiratory complex I intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial complex I activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 partially restores NDUFS4 AS pattern and expression and reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of complex I activity through AS regulation.

molecular biology↗

bioRxiv2020

Nuclear IQGAP1 promotes gastric cancer cell growth by altering the splicing of a cell-cycle regulon in co-operation with hnRNPM

In response to oncogenic signals, Alternative Splicing (AS) regulators such as SR and hnRNP proteins show altered expression levels, subnuclear distribution and/or post-translational modification status, but the link between signals and these changes remains unknown. Here, we report that a cytosolic scaffold protein, IQGAP1, performs this task in response to heat-induced signals. We show that in gastric cancer cells, a nuclear pool of IQGAP1 acts as a tethering module for a group of spliceosome components, including hnRNPM, a splicing factor critical for the response of the spliceosome to heat-shock. IQGAP1 controls hnRNPMs sumoylation, subnuclear localization and the relevant response of the AS machinery to heat-induced stress. Genome-wide analyses reveal that IQGAP1 and hnRNPM co-regulate the AS of a cell cycle-related RNA regulon in gastric cancer cells, thus favouring the accelerated proliferation phenotype of gastric cancer cells. Overall, we reveal a missing link between stress signals and AS regulation.

molecular biology↗