Biology subjects

Tsang, S.

Publications and source records attributed to Tsang, S..

6 recordsLinked to original sources

bioRxiv2025

Salmonella SteD and mammalian SUSD6 use TMEM127 to co-disinhibit the WWP2 E3 ubiquitin ligase

The NEDD4-like E3 ubiquitin ligase, WWP2, is involved in a range of host processes from cell differentiation to T cell immunity. Ligase activity is tightly regulated with WWP2 being held in an autoinhibited state. Binding of a PY motif containing adaptor, an Ndfip, via the WW domains of NEDD4-like E3 ubiquitin ligases leads to their disinhibition. Here, we show that the canonical Ndfip, NDFIP2, requires multiple PY motifs for interaction with and activation of WWP2. In contrast, the single PY-motif containing Ndfips TMEM127 and SUSD6 function as a co-disinhibitory pair. TMEM127 and the Salmonella protein SteD also function as a co-disinhibitory pair. However, SteD interacts with a different region of the WWP2, the C2 domain, and this interaction results in disinhibition of WWP2. These findings demonstrate a range of ways that Ndfips can disinhibit WWP2. To our knowledge, these are the first examples of two Ndfips functioning as co-disinhibitory pairs, and of a bacterial effector that disinhibits an E3 ubiquitin ligase.

cell biology↗

bioRxiv2023

Systematic Pan-cancer Functional Inference and Validation of Hyper, Hypo and Neomorphic Mutations

While the functional effects of many recurrent cancer mutations have been characterized, the TCGA repository comprises more than 10M non-recurrent events, whose function is unknown. We propose that the context specific activity of transcription factor (TF) proteins--as measured by expression of their transcriptional targets--provides a sensitive and accurate reporter assay to assess the functional role of oncoprotein mutations. Analysis of differentially active TFs in samples harboring mutations of unknown significance--compared to established gain (GOF/hypermorph) or loss (LOF/hypomorph) of function--helped functionally characterize 577,866 individual mutational events across TCGA cohorts, including identification of mutations that are either neomorphic (gain of novel function) or phenocopy other mutations (mutational mimicry). Validation using mutation knock-in assays confirmed 15 out of 15 predicted gain and loss of function mutations and 15 of 20 predicted neomorphic mutations. This could help determine targeted therapy in patients with mutations of unknown significance in established oncoproteins.

systems biology↗

bioRxiv2022

Dectin-1 Stimulation Promotes a Distinct Inflammatory Signature in the Setting of HIV-infection and Aging

Dectin-1 is an innate immune receptor that recognizes and binds {beta}-1,3/1,6 glucans on fungi. We evaluated Dectin-1 function in myeloid cells in a cohort of HIV-positive and HIV-negative young and older adults. Stimulation of monocytes with {beta}-D-glucans induced a pro-inflammatory phenotype in monocytes of HIV-infected individuals that was characterized by increased levels of IL-12, TNF-, and IL-6, with some age-associated cytokine increases also noted. Dendritic cells showed a striking HIV-associated increase in IFN- production. These increases in cytokine production paralleled increases in Dectin-1 surface expression in both monocytes and dendritic cells that were noted with both HIV and aging. Differential gene expression analysis showed that HIV-positive older adults had a distinct gene signature compared to other cohorts characterized by a robust TNF- and coagulation response (increased at baseline), a persistent IFN- and IFN-{gamma} response, and an activated dendritic cell signature/M1 macrophage signature upon Dectin-1 stimulation. Dectin-1 stimulation induced a strong upregulation of MTORC1 signaling in all cohorts, although increased in the HIV-Older cohort (stimulation and baseline). Overall, our study demonstrates that the HIV Aging population has a distinct immune signature in response to Dectin-1 stimulation. This signature may contribute to the pro-inflammatory environment that is associated with HIV and Aging.

immunology↗

bioRxiv2022

Epitope Mapping of SARS-CoV-2 Spike Protein Reveals Distinguishable Antibody Binding Activity of Vaccinated and Infected Individuals.

Previous studies have attempted to characterize the antibody response of individuals to the SARS-CoV-2 virus on a linear peptide level by utilizing peptide microarrays. These studies have helped to identify epitopes that have potential to be used for diagnostic tests to identify infected individuals, however, the immunological responses of individuals who have received the currently available Moderna mRNA-1273 or Pfizer BNT162b2 mRNA vaccines have not been characterized. We aimed to identify linear peptides of the SARS-CoV-2 spike protein that elicited high IgG or IgA binding activity and to compare the immunoreactivity of infected individuals to those who received both doses of either vaccines by utilizing peptide microarrays. Our results revealed peptide epitopes of significant IgG binding among recently infected individuals. Some of these peptides are located near functional domains implicated in the high infectivity of SARS-CoV-2. Vaccinated individuals lacked these distinct markers despite overall binding activity being similar.

immunology↗

bioRxiv2022

Platelet response to influenza vaccination reflects effects of aging

Platelets are uniquely positioned as mediators of not only hemostasis but also innate immunity, but how age and alterations in functional status such as frailty influence platelet function during an immune response remains unclear. We assessed the platelet transcriptome in younger (age 21-35) and older (age [≥] 65) adults (including frail and non-frail individuals) following influenza vaccination. Prior to vaccination, we identified an age- and frailty-associated increase in expression of platelet activation and mitochondrial RNAs and decrease in RNAs encoding proteins mediating translation. Using tensor decomposition analysis, we also elucidated dynamic post-vaccination platelet activation and translation signatures associated with age and frailty. At the protein level, enhanced platelet activation was found in non-frail older adults, compared to young individuals both prior to and post-vaccine; but frail adults showed decreased platelet activation compared to non-frail that could reflect the influence of decreased translation RNA expression. Our results reveal an age-dependent alteration in platelet function prior to and post-vaccination that may contribute to age-associated chronic inflammation.

immunology↗

bioRxiv2019

Seasonal Variability and Shared Molecular Signatures of Inactivated Influenza Vaccination in Young and Older Adults

The seasonal influenza vaccine is an important public health tool but is only effective in a subset of individuals. The identification of molecular signatures provides a mechanism to understand the drivers of vaccine-induced immunity. Most previously reported molecular signatures of influenza vaccination were derived from a single age group or season, ignoring the effects of immunosenescence or vaccine composition. Thus, it remains unclear how immune signatures of vaccine response change with age across multiple seasons. Here we profile the transcriptional landscape of young and older adults over five consecutive vaccination seasons to identify shared signatures of vaccine response as well as marked seasonal differences. Along with substantial variability in vaccine-induced signatures across seasons, we uncovered a common transcriptional signature 28 days post-vaccination in both young and older adults. However, gene expression patterns associated with vaccine-induced antibody responses were distinct in young and older adults; for example, increased expression of Killer Cell Lectin Like Receptor B1 (KLRB1; CD161) 28 days post-vaccination positively and negatively predicted vaccine-induced antibody responses in young and older adults, respectively. These findings contribute new insights for developing more effective influenza vaccines, particularly in older adults.

immunology↗