Biology subjects

Jewell, C. P.

Publications and source records attributed to Jewell, C. P..

8 recordsLinked to original sources

bioRxiv2026

SV40 Large T antigen inhibits the host serine protease FAM111A through a zinc-dependent, cleavage-avoiding mechanism

SV40 Large T antigen (LT) is essential for viral replication and a key determinant of host range. This host-range function is mediated by the C-terminal domain (LT-C) through binding to the host serine protease FAM111A, but the underlying mechanism has remained unclear. Here, we report the X-ray crystal structure of the FAM111A serine protease domain in complex with LT-C, revealing the structural basis for direct inhibition of FAM111A. LT-C uses a previously unrecognized zinc-binding motif and a P1-like phenylalanine residue to engage the FAM111A active site through a substrate-mimicking mechanism while avoiding proteolytic cleavage and covalent complex formation. Mutations disrupting either feature abolish FAM111A inhibition and impair SV40 propagation in cells. Consistent with this mechanism, SV40 host restriction requires FAM111A protease activity, which must be antagonized by LT-C for productive infection. Together, these findings define a zinc-dependent, cleavage-avoiding mechanism of protease inhibition that highlights an evolutionary arms race between SV40 and host antiviral proteases.

biochemistry↗

bioRxiv2026

Global Proteomics Investigation of SAMT-247 Targets: An Antiviral Thioester that Acetylates Zinc Finger Proteins

Covalent modification of target proteins is a well-established mechanism of action for small molecule inhibitors. Cysteine residues in particular have been exploited for their reactivity toward electrophilic molecules. SAMT-247 is a mercaptobenzamide thioester that covalently acetylates cysteines in the zinc-coordinating domains of the HIV nucleocapsid protein. This SAMT-247-promoted reaction leads to loss of zinc binding by the protein, with concomitant loss of protein structure and function. Although it has low cytotoxicity in animal models, recent studies have indicated that it affects other protein targets in uninfected cells, for example leading to increased immune cell functions. In this study, global proteomics approaches have been used to better understand other protein targets of SAMT-247. Minimal effects are observed when unstimulated THP-1 monocyte cells were treated with SAMT-247. In contrast, thermal proteome profiling identified 170 proteins with altered thermal stability when THP-1 cells were stimulated with phorbol 12-myristate 13-acetate/Ionomycin (PMA/Iono) before SAMT-247 treatment. Among the affected proteins, 81 contain a zinc-coordinating domain and/or have been shown to have a reactive cysteine residue. Among these, several play a role in cellular metabolism, and Seahorse assays demonstrated that SAMT-247 significantly increased the anti-metabolic and pro-glycolytic effect of PMA/Iono in THP-1 cells. Two of the most-affected proteins were ZC3H7A, a microRNA-binding protein with four zinc finger domains, and MGMT, a DNA damage repair protein with a reactive cysteine. Both proteins were modified by SAMT-247 when tested alone or in the presence of THP-1 cell lysate, indicating that they are bona fide targets of the inhibitor. The low activity of SAMT-247 in unstimulated THP-1 cells is consistent with its low cytotoxicity. The increased effects of SAMT-247 in stimulated immune cells suggests that this molecule could be developed to target diseases other than HIV.

cell biology↗

bioRxiv2025

A modelling assessment for the impact of control measures on highly pathogenic avian influenza transmission in poultry in Great Britain

Since 2020, large-scale outbreaks of highly pathogenic avian influenza (HPAI) H5N1 in Great Britain have resulted in substantial poultry mortality and economic losses. Alongside the costs, the risk of circulation leading to a viral reassortment that causes zoonotic spillover raises additional concerns. However, the precise mechanisms driving transmission between poultry premises and the impact of potential control measures in Great Britain, such as vaccination, are not fully understood. We have developed a spatial transmission model for the spread of HPAI in poultry premises calibrated to infected premises data for the 2022-23 season using Markov chain Monte Carlo. Our results indicate that enhanced biosecurity measures and/or vaccination of the premises surrounding an identified infected premises can substantially reduce the overall number of infected premises. Our findings highlight that enhanced control measures could limit the future impact of HPAI on the poultry industry and reduce the risk of broader health threats.

systems biology↗

bioRxiv2025

A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, with a five-year survival rate of 65%. Oxaliplatin was the first platinum drug shown to improve CRC patient outcomes and is now a common adjuvant therapy for advanced disease, yet 90% of patients develop resistance. Oxaliplatin was developed as a third-generation derivative of cisplatin, but recent evidence points to divergent modes of action. Here, genome-wide CRISPR activation and knockout screens were conducted to identify genetic changes that confer resistance to oxaliplatin in two CRC cell lines with distinct molecular backgrounds (SW620 and RKO). Guide RNAs corresponding to the neutral amino acid transporter SLC43A1 (LAT3) were the most significantly enriched in knockout screens and depleted in activation screens, suggesting a potential role for LAT3 in modulating oxaliplatin resistance. In vitro CRISPR knockout and overexpression of LAT3 in SW620 and RKO cell lines confirm increased resistance or sensitivity to oxaliplatin, respectively. Further analysis demonstrates that increased LAT3 levels corrrelate with increased intracellular levels of oxaliplatin, increased levels of DNA-platinum adducts and DNA damage, demonstrating that enhanced LAT3-mediated uptake of oxaliplatin can exert its expected mechanism of action and induce cytotoxicity. These findings may lead to a better understanding of oxaliplatins mode of action in CRC and can provide new insights into the interplay between essential nutrient uptake and drug transport. STATEMENT OF SIGNIFICANCEOxaliplatin resistance remains a major clinical challenge for CRC treatment. Our study identified a novel role for LAT3 as a modulator of oxaliplatin sensitivity, offering new insights into drug resistance mechanisms.

cancer biology↗

bioRxiv2024

A real-time forecasting framework for emerging infectious diseases affecting animal populations

Infectious disease forecasting has become increasingly important in public health, as demonstrated during the COVID-19 pandemic. However, forecasting tools for emergency animal diseases, particularly those offering real-time decision support when parameters governing disease dynamics are unknown, remain limited. We introduce a generalised modelling framework for near-real-time forecasting of the temporal and spatial spread of infectious livestock diseases using data from the early stages of an outbreak. We applied the framework to the 2007 equine influenza outbreak in Australia, generating prediction targets at three timepoints across four regional clusters. Our targets included future daily case counts, outbreak size, peak timing and duration, and spatial distributions of future spread. We evaluated how well the forecasts predicted daily cases and the spatial distribution of case counts, using skill scores as a benchmark for future model improvements. Forecast accuracy, certainty, and skill improved significantly after the outbreaks peak, while early predictions were more variable, suggesting that pre-peak forecasts should be interpreted with caution. Spatial forecasts maintained positive skill throughout the outbreak, supporting their use in guiding response priorities. This framework provides a tool for real-time decision-making during livestock disease outbreaks and establishes a foundation for future refinements and applications to other animal diseases.

bioinformatics↗

bioRxiv2023

The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species

Although few resistance mechanisms for histone deacetylase inhibitors (HDACis) have been described, we recently demonstrated that TMT1A (formerly METTL7A) and TMT1B (formerly METTL7B) can mediate resistance to HDACis with a thiol as the zinc-binding group by methylating and inactivating the drug. TMT1A and TMT1B are poorly characterized, and their normal physiological role has yet to be determined. As animal model systems are often used to determine the physiological function of proteins, we investigated whether the ability of these methyltransferases to methylate thiol-based HDACis is conserved across different species. We found that TMT1A was conserved across rats, mice, chickens, and zebrafish, displaying 85.7%, 84.8%, 60.7% and 51.0% amino acid sequence identity, respectively, with human TMT1A. Because TMT1B was not found in the chicken or zebrafish, we focused our studies on the TMT1A homologs. HEK-293 cells were transfected to express mouse, rat, chicken, or zebrafish homologs of TMT1A and all conferred resistance to the thiol-based HDACIs NCH-51, KD-5170 and romidepsin compared to empty vector-transfected cells. Additionally, all homologs blunted the downstream effects of HDACi treatment such as increased p21 expression, increased acetylated histone H3, and cell cycle arrest. Increased levels of dimethylated romidepsin were also found in the culture medium of cells transfected to express any of the TMT1A homologs after a 24 h incubation with romidepsin compared to empty-vector transfected cells. Our results indicate that the ability of TMT1A to methylate molecules is conserved across species. Animal models may therefore be useful in elucidating the role of these enzymes in humans.

pharmacology and toxicology↗

bioRxiv2019

Intraspecific genetic variation underlying postmating reproductive barriers between species in the wild tomato clade (Solanum sect. Lycopersicon)

A goal of speciation genetics is to understand how the genetic components underlying interspecific reproductive barriers originate within species. Unilateral incompatibility (UI) is a postmating prezygotic barrier in which pollen rejection in the female reproductive tract (style) occurs in only one direction of an interspecific cross. Natural variation in the strength of UI has been observed among populations within species in the wild tomato clade. In some cases, molecular loci underlying self-incompatibility (SI) are associated with this variation in UI, but the mechanistic connection between these intra- and inter-specific pollen rejection behaviors is poorly understood in most instances. We generated an F2 population between SI and SC genotypes of a single species, Solanum pennellii, to examine the genetic basis of intraspecific variation in the strength of UI against other species, and to determine whether loci underlying SI are genetically associated with this variation. We found that F2 individuals vary in the rate at which UI rejection occurs. One large effect QTL detected for this trait co-localized with the SI-determining S-locus. Moreover, individuals that expressed S-RNase--the S-locus protein involved in SI pollen rejection--in their styles had much more rapid UI responses compared to those without S-RNase protein. Our analysis shows that intraspecific variation at mate choice loci--in this case at loci that prevent self-fertilization--can contribute to variation in the strength of interspecific isolation, including postmating prezygotic barriers. Understanding the nature of such standing variation can provide insight into the accumulation of these barriers between diverging lineages.

evolutionary biology↗

bioRxiv2018

Robustness of local control strategies under modelling uncertainties: the 2004 avian infuenza H5N1 outbreak in Thailand

The Highly Pathogenic Avian Influenza (HPAI) subtype H5N1 virus persists in many countries and has been circulating in poultry, wild birds. In addition, the virus has emerged in other species and frequent zoonotic spillover events indicate that there remains a significant risk to human health. It is crucial to understand the dynamics of the disease in the poultry industry to develop a more comprehensive knowledge of the risks of transmission and to establish a better distribution of resources when implementing control. In this paper, we develop a set of mathematical models that simulate the spread of HPAI H5N1 in the poultry industry in Thailand, utilising data from the 2004 epidemic. The model that incorporates the intensity of duck farming when assessing transmision risk provides the best fit to the spatiotemporal characteristics of the observed outbreak, implying that intensive duck farming drives transmission of HPAI in Thailand. We also extend our models using a sequential model fitting approach to explore the ability of the models to be used in \"real time\" during novel disease outbreaks. We conclude that, whilst predictions of epidemic size are estimated poorly in the early stages of disease outbreaks, the model accurately predicts the preferred control policy that should be deployed to minimise the impact of the disease.

epidemiology↗