Biology subjects

Edmonds, K.

Publications and source records attributed to Edmonds, K..

3 recordsLinked to original sources

bioRxiv2026

Distinct functions of PBRM1 and BAP1 reconcile the course of kidney cancer evolution and disease progression

Clear cell renal cell carcinoma (ccRCC) progresses along two predominant evolutionary trajectories, defined by PBRM1 ([~]40%) or BAP1 ([~]15%) mutations on a VHL-inactivated background. They have distinct patterns of evolutionary tempo and mode, and vastly different clinical outcomes, yet the underlying genotype-specific molecular phenotypic programmes are unknown. We established a patient-derived preclinical model biobank that captures the genetic diversity of ccRCC. Through integrative analyses of preclinical models and tumour bulk and single cell profiling, we identified transcriptional and epigenetic changes specific to PBRM1- and BAP1-driven ccRCC. Modelling PBRM1 loss in vitro demonstrates that it reinforces renal lineage identity and maintains progenitor-like cell state. In contrast, BAP1 loss drives inflammatory signalling and chromosomal instability. These insights reconcile the distinct evolutionary modes (branched versus punctuated), tempo (slow versus fast) and clinical outcomes associated with PBRM1 and BAP1 mutations, respectively, establishing a framework for patient stratification and genotype-directed therapeutic development.

cancer biology↗

bioRxiv2021

Human metapneumovirus P protein independently drives phase separation and recruits N protein to liquid-like inclusion bodies

Human metapneumovirus (HMPV) inclusion bodies (IBs) are dynamic structures required for efficient viral replication and transcription. The minimum components needed to form IB-like structures in cells are the nucleoprotein (N) and the tetrameric phosphoprotein (P). HMPV P binds to two versions of N protein in infected cells: C-terminal P residues interact with oligomeric, RNA-bound N (N-RNA), and N-terminal P residues interact with monomeric N (N0) to maintain a pool of protein to encapsidate new RNA. Recent work on other negative-strand viruses has suggested that IBs are liquid-like organelles formed via liquid-liquid phase separation (LLPS). Here, HMPV IBs in infected or transfected cells were shown to possess liquid organelle properties, such as fusion and fission. Recombinant versions of HMPV N and P proteins were purified to analyze the interactions required to drive LLPS in vitro. Purified HMPV P was shown to form liquid droplets in the absence of other protein binding partners, a novel finding compared to other viral systems. Removal of nucleic acid from purified P altered phase separation dynamics, suggesting that nucleic acid interactions also play a role in IB formation. HMPV P also recruits monomeric N (N0-P) and N-RNA to IBs in vitro. These findings suggest that, in contrast to what has been reported for other viral systems, HMPV P acts as a scaffold protein to mediate multivalent interactions with monomeric and oligomeric HMPV N to promote phase separation of IBs. IMPORTANCEHuman metapneumovirus (HMPV) is a leading cause of respiratory disease among children, immunocompromised individuals, and the elderly. Currently, no vaccines or antivirals are available for treatment of HMPV infections. Cytoplasmic inclusion bodies (IBs), where HMPV replication and transcription occur, represent a promising target for the development of novel antivirals. The HMPV nucleoprotein (N) and phosphoprotein (P) are the minimal components needed for IB formation in eukaryotic cells. However, interactions that regulate the formation of these dynamic structures are poorly understood. Here, we showed that HMPV IBs possess the properties of liquid organelles and that purified HMPV P phase separates independently in vitro. Our work suggests that HMPV P phase separation dynamics are altered by nucleic acid. We provide strong evidence that, unlike results reported from other viral systems, HMPV P alone serves as a scaffold for multivalent interactions with monomeric (N0) and oligomeric (N-RNA) HMPV N for IB formation.

microbiology↗

bioRxiv2021

Effect of mutations in the SARS-CoV-2 spike protein on protein stability, cleavage, and cell-cell fusion function

The SARS-CoV-2 spike protein (S) is the sole viral protein responsible for both viral binding to a host cell and the membrane fusion event needed for cell entry. In addition to facilitating fusion needed for viral entry, S can also drive cell-cell fusion, a pathogenic effect observed in the lungs of SARS-CoV-2 infected patients. While several studies have investigated S requirements involved in viral particle entry, examination of S stability and factors involved in S cell-cell fusion remain limited. We demonstrate that S must be processed at the S1/S2 border in order to mediate cell-cell fusion, and that mutations at potential cleavage sites within the S2 subunit alter S processing at the S1/S2 border, thus preventing cell-cell fusion. We also identify residues within the internal fusion peptide and the cytoplasmic tail that modulate S cell-cell fusion. Additionally, we examine S stability and protein cleavage kinetics in a variety of mammalian cell lines, including a bat cell line related to the likely reservoir species for SARS-CoV-2, and provide evidence that proteolytic processing alters the stability of the S trimer. This work therefore offers insight into S stability, proteolytic processing, and factors that mediate S cell-cell fusion, all of which help give a more comprehensive understanding of this highly sought-after therapeutic target.

microbiology↗