Biology subjects

Ward, H.

Publications and source records attributed to Ward, H..

3 recordsLinked to original sources

bioRxiv2025

The acidic N-terminus of HHARI and neddylation are essential for the activation and maintenance of RIG-I-mediated type I interferon response

Human homolog of Ariadne (HHARI) is a RING-between-RING ubiquitin E3 ligase which interacts with cullin-RING E3 ligase (CRL) complexes. HHARI has been implicated in the type-I interferon anti-viral response. However, how HHARI drives interferon signalling is not fully understood and the function of the unique, highly conserved acidic N-terminal domain of the protein is unknown. Here, we show that HHARI stimulates interferon-{beta} secretion and autocrine type-I interferon signalling by directly targeting the viral RNA sensor RIG-I (Retinoic Acid-Inducible Gene I) in a neddylation-dependent manner. This suggests that neddylation inhibition could be used to treat interferonopathies and related diseases. Truncated HHARI containing only the N-terminal acidic/UBA-like domains retained the ability to induce interferon signalling in a neddylation-dependent mechanism. HHARI-mediated interferon-{beta} secretion was enhanced by overexpression of cullins 1-5. The N-terminal acidic/UBA-like domain of HHARI is critical for RIG-I activation and interferon signalling, as removal of these domains inactivated the pro-interferon phenotype. We propose a mechanism by which the N-terminus of HHARI interacts with all neddylated cullins leading to endogenous HHARI activation. This suggests a model in which the N-terminus of HHARI unlocks and activates neddylated cullins, which in turn are required for activation of HHARI itself. As cullins typically form modular cullin-RING ligase super-assemblies our findings imply that the HHARI N-terminus domain is a critical regulator of the versatile CRL system, which, through widespread protein ubiquitylation, controls many eukaryotic cell functions.

immunology↗

bioRxiv2023

VmPFC supports persistence during goal pursuit through selective attention

Striking the balance between persistence with a goal and flexibility in the face of better options is critical for effectively organizing behaviour across time. While people are often biased towards completing their current goal (e.g. sunk cost biases), it is unclear how these biases occur at a mechanistic level, still allowing for some flexibility for goal abandonment. We propose that ventromedial prefrontal cortex (vmPFC) plays a critical role in orienting attention towards a current goal, prioritising goal completion but allowing for abandonment, particularly when the current goal fails. We developed a novel incremental goal pursuit task to study goal-directed attention and action in healthy individuals with functional magnetic resonance imaging (fMRI), and in an independent group of individuals with brain lesions. The task required participants to make sequential decisions between continuing to persist with a current goal (commitment), versus abandoning progress for a better alternative goal (flexibility). We show that individuals who persist more show greater goal-oriented attention outside the decision period. Increasing attentional capture by the current goal is also revealed in decision-making: people remain more likely to abandon from frustration (collapse of value of the current goal) than from temptation (attraction from valuable alternative goals). Strikingly, we find that our stable inter-individual metrics of persistence and goal-oriented attention were both predicted by baseline activity in vmPFC, tracking goal progress. We present converging evidence from an independent lesion patient study demonstrating the causal involvement of vmPFC in goal persistence: damage to the vmPFC reduces biases to over-persist with the current goal, leading to a performance benefit in our task.

neuroscience↗

bioRxiv2018

MaGIC: a machine learning tool set and web application for monoallelic gene inference from chromatin

SummaryA large fraction of human and mouse autosomal genes are subject to random monoallelic expression (MAE), an epigenetic mechanism characterized by allele-specific gene expression that varies between clonal cell lineages. MAE is highly cell-type specific, and mapping it in a large number of cell and tissue types can provide insight into its biological function. Its detection, however, remains challenging. We previously reported that a sequence-independent chromatin signature identifies, with high sensitivity and specificity, genes subject to MAE in multiple tissue types using readily available ChIP-seq data. Here we present an implementation of this method as a user-friendly, open-source software pipeline for monoallelic gene inference from chromatin (MaGIC).\n\nAvailability and implementationThe source code for the MaGIC pipeline and the Shiny app is available at https://github.com/gimelbrantlab/magic.\n\nContactsebastien_vigneau@dfci.harvard.edu, gimelbrant@mail.dfci.harvard.edu

bioinformatics↗