Biology subjects

Mendoza, M. B.

Publications and source records attributed to Mendoza, M. B..

5 recordsLinked to original sources

bioRxiv2025

Concerted remodelling of the postsynaptic spine and RNA granule by cLTP

Synaptic plasticity is the cellular foundation of learning and memory and, for these plastic changes to be stabilised into long-term memory, proteins must be synthesised at the synapse1,2. RNA granules ensure that specific mRNAs are delivered and translated at the right time and place3,4, but the signalling mechanisms linking synaptic activation to local translation are still largely unknown. Here, to investigate how postsynaptic signals modulate the RNA granule, we employed a spatially-restricted biotinylation approach to quantify protein accessibility and proximity in the postsynaptic and RNA granule subproteomes. Upon chemical long-term potentiation (cLTP), we observed a sharp increase in the accessibility of ribosomes, translation factors and RNA binding proteins belonging to the RNA granule. Similarly, strong alterations were observed in proteins of the postsynaptic density, but mostly in those involved in signalling. Specific proximity to DBN1 and IGF2BP1 as postsynaptic and RNA granule reporters unveiled a shift of the translation machinery towards the postsynaptic compartment, whereas specific translation initiation factors and RNA helicases displayed marked changes in their proximity to DBN1 and/or IGF2BP1. Finally, alteration of synapse development and signalling by DBN1 downregulation caused a highly significant decrease in the proximity of RNA granule proteins to IGF2BP1 after synaptic stimulation, establishing a causal link between postsynaptic events and RNA granule dynamics.

neuroscience↗

bioRxiv2024

Purine and pyrimidine synthesis differently affect the strength of the inoculum effect for aminoglycoside and B-lactam antibiotics.

The inoculum effect has been observed for nearly all antibiotics and bacterial species. However, explanations accounting for its occurrence and strength are lacking. We previously found that growth productivity, which captures the relationship between [ATP] and growth, can account for the strength of the inoculum effect for bactericidal antibiotics. However, the molecular pathway(s) underlying this relationship, and therefore determining the inoculum effect, remain undiscovered. We show that nucleotide synthesis can determine the relationship between [ATP] and growth, and thus the strength of inoculum effect in an antibiotic class-dependent manner. Specifically, and separate from activity through the tricarboxylic acid cycle, we find that transcriptional activity of genes involved in purine and pyrimidine synthesis can predict the strength of the inoculum effect for {beta}-lactam and aminoglycosides antibiotics, respectively. Our work highlights the antibiotic class-specific effect of purine and pyrimidine synthesis on the severity of the inoculum effect and paves the way for intervention strategies to reduce the inoculum effect in the clinic.

microbiology↗

bioRxiv2023

KIS counteracts PTBP2 and regulates alternative exon usage in neurons

Alternative RNA splicing is an essential and dynamic process to control neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here we show that KIS, a brain-enriched kinase with a domain shared by splicing factors, controls exon usage in differentiated neurons at a genome-wide level. KIS phosphorylates the splicing regulator PTBP2 complex and markedly counteracts its role in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from key co-regulators and hinders its RNA-binding capacity. Taken together, our data provide new insights into the post-translational control of splicing regulators and uncover an essential role of KIS in setting alternative exon usage in neurons.

molecular biology↗

bioRxiv2020

eEF1A2 controls local translation and actin dynamics in structural synaptic plasticity

Synaptic plasticity involves structural modifications in dendritic spines. Increasing evidence suggests that structural plasticity is modulated by local protein synthesis and actin remodeling in a synapsis-specific manner. However, the precise molecular mechanisms connecting synaptic stimulation to these processes in dendritic spines are still unclear. In the present study, we demonstrate that the configuration of phosphorylation sites in eEF1A2, an essential translation elongation factor in neurons, is a key modulator of structural plasticity in dendritic spines. A mutant that cannot be phosphorylated stimulates translation but reduces actin dynamics and spine density. By contrast, the phosphomimetic variant loosens its association with F-actin and becomes inactive as a translation elongation factor. Metabotropic glutamate receptor signaling triggers a transient dissociation of eEF1A2 from its GEF protein in dendritic spines, in a phospho-dependent manner. We propose that eEF1A2 establishes a crosstalk mechanism that coordinates local translation and actin dynamics during spine remodeling.

neuroscience↗

bioRxiv2020

Stress granules display bistable dynamics modulated by Cdk

Stress granules are conserved biomolecular condensates that originate in response to many stress conditions. These membraneless organelles contain nontranslating mRNAs and a diverse subproteome, but our knowledge on their regulation and functional relevance is still incipient. Here we describe a mutual-inhibition interplay between stress granules and Cdc28, the budding yeast Cdk. Amongst Cdc28 interactors acting as negative modulators of Start we have identified Whi8, an RNA-binding protein that localizes to SGs and recruits the mRNA of CLN3, the most upstream G1 cyclin, for efficient translation inhibition and Cdk inactivation under stress. However, Whi8 also contributes to recruiting Cdc28 to SGs, where it acts to promote their dissolution. As predicted by a mutual-inhibition framework, the SG constitutes a bistable system that is modulated by Cdk. Since mammalian cells display a homologous mechanism, we propose that the opposing functions of specific mRNA-binding proteins and Cdks subjugate SG dynamics to a conserved hysteretic switch.

cell biology↗