Biology subjects

Tweedie, A.

Publications and source records attributed to Tweedie, A..

3 recordsLinked to original sources

bioRxiv2026

XRN1 couples RNA granule remodelling to global mRNA decay triggered by the activity of a viral endoribonuclease

Cytoplasmic mRNA turnover is a fundamental determinant of gene expression, yet the spatial organisation of RNA decay remains unresolved. Although decay factors are enriched in processing (P)-bodies, whether these condensates actively mediate mRNA degradation or serve primarily as storage compartments remains controversial. Here, we exploit the alphaherpesvirus endoribonuclease, virion host shutoff (vhs), to synchronously trigger rapid, global cytoplasmic mRNA accompanied by nuclear relocalisation of the poly(A)-binding protein PABPC1. Expression of vhs caused the dispersal of P-bodies, but when the 5' to 3' exonuclease XRN1 was depleted, PABPC1 remained in the cytoplasm, and P-bodies stayed intact, associating with previously undetected G3BP1-dependent RNA granules. Similarly, catalytically inactive vhs failed to disperse P-bodies but instead induced RNA granules that also contained vhs itself and recruited decay factors in an XRN1-dependent manner. Translational shutoff by this endoribonuclease did not require RNA cleavage, G3BP1 condensation or XRN1 activity supporting a sequential model in which translational arrest precedes endonucleolytic cleavage, promoting transient RNA granules that engage P-bodies and XRN1-dependent machinery for rapid mRNA degradation within the granules, thereby precluding the biogenesis of deleterious RNA condensates.

cell biology↗

bioRxiv2024

Translational arrest and mRNA decay are independent activities of alphaherpesvirus virion host shutoff proteins

The herpes simplex virus 1 (HSV1) virion host shutoff (vhs) protein is an endoribonuclease that regulates the translational environment of the infected cell, by inducing the degradation of host mRNA via cellular exonuclease activity. To further understand the relationship between translational shutoff and mRNA decay, we have used ectopic expression to compare HSV1 vhs (vhsH) to its homologues from four other alphaherpesviruses - varicella zoster virus (vhsV), bovine herpesvirus 1 (vhsB), equine herpesvirus 1 (vhsE) and Mareks disease virus (vhsM). Only vhsH, vhsB and vhsE induced degradation of a reporter luciferase mRNA, with polyA+ in situ hybridisation indicating a global depletion of cytoplasmic polyA+ RNA and a concomitant increase in nuclear polyA+ RNA and the polyA tail binding protein PABPC1 in cells expressing these variants. By contrast, vhsV and vhsM failed to induce reporter mRNA decay and polyA+ depletion, but rather, induced cytoplasmic G3BP1 and polyA+ mRNA-containing granules and phosphorylation of the stress response proteins eIF2 and protein kinase R. Intriguingly, regardless of their apparent endoribonuclease activity, all vhs homologues induced an equivalent general blockade to translation as measured by single cell puromycin incorporation. Taken together, these data suggest that the activities of translational arrest and mRNA decay induced by vhs are separable and we propose that they represent sequential steps of the vhs host interaction pathway.

microbiology↗

bioRxiv2021

Novel Hendra virus variant detected by sentinel surveillance of Australian horses.

A novel Hendra virus (HeV) variant, not detected by routine testing, was identified and isolated from a Queensland horse that suffered acute, fatal disease consistent with HeV infection. Whole genome sequencing and phylogenetic analysis demonstrated the variant to have ~83% nucleotide identity to the prototype HeV strain. An updated RT-qPCR assay was designed for routine HeV surveillance. In silico and in vitro comparison of the receptor-binding protein with prototypic HeV showed that the human monoclonal antibody m102.4 used for post-exposure prophylaxis, as well as the current equine vaccine, should be effective against this variant. Genetic similarity of this virus to sequences detected from grey-headed flying-foxes suggests the variant circulates at-least in this species. Studies determining infection kinetics, pathogenicity, reservoir-species associations, viral-host co-evolution and spillover dynamics for this virus are urgently needed. Surveillance and biosecurity practices should be updated to appreciate HeV spillover risk across all regions frequented by flying foxes.

molecular biology↗