Biology subjects

Richardson, G.

Publications and source records attributed to Richardson, G..

4 recordsLinked to original sources

bioRxiv2026

Endothelial AMBRA1 loss contributes to vascular dysregulation facilitating metastatic progression in early-stage melanoma

Validated biomarkers for identifying patients with early-stage melanomas at high risk of metastasis are limited. We have previously shown that loss of Activating Molecule in Beclin-1-Regulated Autophagy (AMBRA1) and loricrin in the epidermal microenvironment is associated with tumour recurrence. Here we show that endothelial AMBRA1 deficiency contributes to vascular dysfunction and melanoma progression. Melanoma-conditioned media or exposure to TGF{beta}1-3 ligands induced post-transcriptional loss of AMBRA1 in endothelial cells. Transcriptomic profiling in both in vitro and human melanoma single-cell RNA sequencing datasets showed activation of cell-cycle and metabolic programmes alongside suppression of endothelial junction, adhesion and immune-supportive pathways in AMBRA1-deficient endothelial cells. Functionally, AMBRA1 loss increased endothelial cell proliferation, accelerated early tubulogenesis, impaired three-dimensional spheroid adhesion, stabilised endothelial-to-mesenchymal transition-associated transcription factors Slug and Snail, and reduced Claudin-5, VE-cadherin and N-cadherin, indicative of endothelial plasticity and dysfunction. Furthermore, loss of AMBRA1 in a subset of intratumoural and peritumoural blood and lymphatic vessels correlated significantly with metastatic progression in a cohort of 121 non-ulcerated primary AJCC stage I/II melanomas classified as AMBLor at-risk. Collectively, these findings position endothelial AMBRA1 as a regulator of vascular plasticity, dysfunction, and immune-supportive endothelial function in early-stage melanomas, and a marker of a permissive microenvironment associated with metastasis.

cancer biology↗

bioRxiv2026

δ-catenin controls layer-specific transcriptional maturation of astrocytes via Zbtb20

Coordinated maturation of diverse neural cell types drives mammalian cortical circuit development. Disruption of this coordination is a hallmark of human neurodevelopmental disorders, yet mechanisms that synchronize transcriptional maturation across cell types remain poorly understood. Here, we identify {delta}-catenin (Ctnnd2), a component of adherens junctions, that links cell-cell interactions to transcriptional regulation. Using single-nucleus and spatial transcriptomics, we show that {delta}-catenin loss disrupts transcriptional maturation across neural cell types, particularly in astrocytes. {delta}-catenin loss impairs acquisition of layer-specific astrocyte identities and prolongs ocular dominance plasticity, indicating impaired circuit stabilization. Mechanistically, we identify the BTB/POZ transcription factor Zbtb20, which is enriched in glial cells, as a key regulator of this process. {delta}-catenin loss increases Zbtb20 expression, redistributes its genome-wide binding, and dysregulates its target genes. Together, these findings support a model in which {delta}-catenin regulates Zbtb20-dependent transcriptional programs to establish layer-specific astrocyte identities in coordination with developing cortical circuits. SUMMARYSejourne et al report that loss of the adherens junction protein {delta}-catenin prolongs ocular dominance plasticity and disrupts astrocyte and oligodendrocyte transcriptional identity. The underlying mechanism seems to rely on the glia-enriched transcription factor Zbtb20, which is upregulated and redistributed upon {delta}-catenin loss, resulting in altered expression of its target genes.

cell biology↗

bioRxiv2025

Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation

Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that targets the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.

cell biology↗

bioRxiv2024

PIRATE: Plundering AlphaFold Predictions to Automate Protein Engineering

An important characteristic for many proteins is the presence of flexible loops or linkers known as intrinsically disordered regions. One downside to many of the state-of-the-art disorder prediction approaches is that they require significant computational time for each inference. Here, we introduce three novel surrogate models trained on AlphaFold2 predictions that rapidly encode local, regional, and global structural properties directly from primary sequence. We combined the outputs from these surrogate models, in an approach we term PIRATE, and show that this approach approximates the performance of AlphaFold2 for disorder prediction. Additionally, we show that PIRATE is much more sensitive to the effects of point mutants on disorder at distal sites than many current disorder prediction methods. Furthermore, we show that in the context of a greedy exploration algorithm, PIRATEs ability to evaluate differences between point mutants makes it ideal for automating disorder-related protein engineering tasks.

biochemistry↗