Biology subjects

Beekmayer-Dhillon, A.

Publications and source records attributed to Beekmayer-Dhillon, A..

2 recordsLinked to original sources

bioRxiv2025

UCHL3 regulates subgenomic flaviviral RNA condensates to promote virus propagation

In this study we demonstrate a previously uncharacterised post-translational regulatory mechanism governing flavivirus replication through the deubiquitylating enzyme ubiquitin C-terminal hydrolase L3 (UCHL3). Using activity-based protein profiling, we identified UCHL3 as a key cellular factor activated during Zika virus (ZIKV) and dengue virus (DENV) infections. CRISPR-Cas9 knockout experiments demonstrated that UCHL3 deficiency impairs flavivirus replication and viral protein expression across multiple cellular models. The underlying molecular mechanism involves UCHL3-mediated stabilisation of subgenomic flaviviral RNA (sfRNA)-containing biomolecular condensates. Through biotinylated sfRNA-interactome capture assays, we show that UCHL3 physically interacts with sfRNA-containing ribonucleoprotein complexes alongside G3BP1. Importantly, UCHL3 depletion triggers inappropriate RNase L activation, leading to sfRNA relocalisation from protective P-bodies to degradative compartments, such as RNase L-induced bodies (RLBs) as reported previously, resulting in viral RNA decay. Our rescue experiments confirmed that RNase L knockdown restores viral replication in UCHL3-deficient cells. This pro-viral effect of UCHL3 operates through interferon-independent mechanisms, as demonstrated by persistent replication defects even upon exogenous interferon treatment. This work therefore identifies UCHL3 as a molecular switch controlling the balance between pro-viral and antiviral RNA condensates, representing a promising host dependency factor for broad-spectrum flavivirus intervention strategies.

cell biology↗

bioRxiv2024

Vagal TRPV1+ sensory neurons regulate myeloid cell dynamics and protect against influenza virus infection

Influenza viruses are a major global cause of morbidity and mortality. Vagal TRPV1+ nociceptive sensory neurons, which innervate the airways, are known to mediate defenses against harmful agents. However, their function in lung antiviral defenses remains unclear. Our study reveals that both systemic and vagal-specific ablation of TRPV1+ nociceptors reduced survival in mice infected with influenza A virus (IAV), despite no significant changes in viral burden or weight loss. Mice lacking nociceptors showed exacerbated lung pathology and elevated levels of pro-inflammatory cytokines. The increased mortality was not attributable to the loss of the TRPV1 ion channel or neuropeptides CGRP or substance P. Immune profiling through flow cytometry and single-cell RNA sequencing identified significant nociceptor deficiency-mediated changes in the lung immune landscape, including an expansion of neutrophils and monocyte-derived macrophages. Transcriptional analysis revealed impaired interferon signaling in these myeloid cells and an imbalance in distinct neutrophil sub-populations in the absence of nociceptors. Furthermore, anti-GR1-mediated depletion of myeloid cells during IAV infection significantly improved survival, underscoring a role of nociceptors in preventing pathogenic myeloid cell states that contribute to IAV-induced mortality. One Sentence Summary: TRPV1+ neurons facilitate host survival from influenza A virus infection by controlling myeloid cell responses and immunopathology.

immunology↗