Biology subjects

Nourse, J.

Publications and source records attributed to Nourse, J..

3 recordsLinked to original sources

bioRxiv2023

The IRE1α-endonuclease regulates PD-1 expression through a novel XBP1/miRNA-34a axis within Natural Killer cells

Activation of the IRE1-endonuclease is critical for Natural Killer (NK)-cell function. We describe a novel regulatory role for IRE1-endonuclease in fine-tuning NK-cell effector functions through an inter-connected activation of the transcription factor XBP1s and inhibition of microRNA-34a-5p (miR-34a-5p) to modulate PD-1 immune checkpoint expression. NK-cells, when exposed to cancer cells, activate IRE1-endonuclease mediated decay of miR-34a-5p. This reduces miR-34a-5p and consequently increases the expression of the target genes XBP1 and PD-1. IRE1-endonuclease activation not only enhances NK-cell effector function but also promotes PD-1 expression. PD-1 is itself directly regulated by miR-34a-5p, which binds to the 3UTR of PD-1 messenger RNA to repress PD-1 protein at the NK-cell surface. IRE1-pathway activation is impaired in the NK-cells of patients with Hodgkin Lymphoma, and miR-34a-5p and PD-1 expression are inversely correlated. The IRE1-pathway plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within NK-cells, that is disrupted in cancer patients.

cancer biology↗

bioRxiv2021

Non-invasive imaging of gene expression and protein secretion dynamics in living mice

The topology of gene expression and protein localization is a crucial characteristic of life, where the spatiotemporal dynamic of secretory proteins instruct higher order organization, including the orchestration of developmental and adaptive programs. However tools to non-invasively interrogate the fate of secretory proteins in vivo are scarce. Here we introduce a genetic tagging strategy for in vivo imaging of the secretion and expression dynamics of secretory proteins in living animals. Applying this to a prototypical liver-derived secretory protein, we demonstrate that this approach, combined with optical in-vivo imaging, uncovers extrahepatic prothrombin expression in multiple novel anatomical sites (including testes, placenta, brain, kidney, heart and lymphatic system) and in emerging tumors, resulting in significant amounts of tumor-derived prothrombin in the blood with procoagulant properties. Syngeneic cell lines from this mouse model enable unravelling regulatory mechanisms in high resolution, and in a scalable format ex vivo. Beyond discovering new functions of proteins in a targeted manner, this model allows identifying rheostats in the cross-talk between gene expression and availability of a secretory protein. It is also a valuable resource for uncovering novel (tissue-specific) therapeutic vulnerabilities.

cell biology↗

bioRxiv2018

A novel rationale for targeting FXI: Insights from the hemostastic miRNA targetome for emerging anticoagulant strategies

Therapeutic targeting of blood coagulation is a challenging task as it interferes with the delicate balance of pro- and anticoagulant activities. Anticoagulants are employed in millions of thrombophilic patients worldwide each year. The treatment and prevention of venous thromboembolism has changed drastically with the replacement of traditional anticoagulant vitamin K antagonists by direct oral anticoagulants (DOACs), which selectively target coagulation factors Xa or IIa. However for a growing population with comorbidities satisfying therapeutic options are still lacking and the quest for novel therapeutics continues. Recently targeting factors XI or XII have emerged as new therapeutic strategies. As these factors play important roles in thrombosis, nevertheless are practically functionally dispensable for hemostasis, they may potentially overcome the functional obstacle of treating or preventing thrombosis without affecting hemostasis. Based on the recent elucidation of the hemostatic miRNA targetome, we introduce and discuss a hitherto unrecognized rationale for the therapeutic targeting of factor XI. This is based on mimicking endogenous factor XI expression control by therapeutic delivery of miRNA mimics. We discuss the functional difference between various gene targeting approaches, and propose the hemostatic system to represent an ideal model for assessment of the efficacy and safety of such therapeutic components, ushering in a novel therapeutic era with broad applicability.

pharmacology and toxicology↗