A5076196252- Ubiquitin and proteasome pathways
- Malaria Research and Control
- Immune Cell Function and Interaction
- Mosquito-borne diseases and control
- Peptidase Inhibition and Analysis
- Autophagy in Disease and Therapy
- HIV Research and Treatment
- Toxoplasma gondii Research Studies
- Parasitic Diseases Research and Treatment
- Glycosylation and Glycoproteins Research
- Genetics and Neurodevelopmental Disorders
- Enzyme Structure and Function
- Mitochondrial Function and Pathology
- Immunotherapy and Immune Responses
- Insect symbiosis and bacterial influences
- Muscle Physiology and Disorders
- Endoplasmic Reticulum Stress and Disease
- Parasite Biology and Host Interactions
- Parasites and Host Interactions
- Trypanosoma species research and implications
- Biochemical and Molecular Research
- HIV/AIDS drug development and treatment
- Biotin and Related Studies
- Complement system in diseases
- Metabolism and Genetic Disorders
University of Cambridge
2016-2025
Imperial College London
2011-2016
Institute of Molecular and Cell Biology
2012
Massachusetts General Hospital
2010
Office of Infectious Diseases
2010
Massachusetts Institute of Technology
2009
Whitehead Institute for Biomedical Research
2006-2008
London School of Hygiene & Tropical Medicine
2002-2003
Harvard University
2003
Abstract To determine the potential contribution of innate immune responses to early proinflammatory cytokine response Plasmodium falciparum malaria, we have examined kinetics and cellular sources IFN-γ production in human PBMC activation by intact, infected RBC (iRBC) or freeze-thaw lysates P. schizonts. Infected erythrocytes induce a more rapid intense from malaria-naive than do schizont correlating with iRBC CD3−CD56+ NK cell population produce IFN-γ. IFN-γ+ cells are detectable within 6...
Abstract Human NK cells are the earliest source of protective cytokine IFN-γ when PBMC from nonimmune donors exposed to Plasmodium falciparum-infected RBC (iRBC) in vitro. In this study, we show that human form stable conjugates with iRBC but not uninfected and induction synthesis is dependent on direct contact between cell iRBC. respond only presence a IL-12/IL-18 subset preferentially express high levels lectin-like receptor CD94/NKG2A. There heterogeneity their ability DNA analysis has...
Abstract Immature dendritic cells (DCs) capture exogenous Ags in the periphery for eventual processing endolysosomes. Upon maturation by TLR agonists, DCs deliver peptide-loaded class II MHC molecules from these compartments to cell surface via long tubular structures (endolysosomal tubules). The nature and rules that govern movement of DC are unknown. In this study, we demonstrate tubules contain multiple proteins including LAMP1, a lysosomal resident protein, as well CD63 CD82, members...
Post-translational modification of proteins by ubiquitin or ubiquitin-like polypeptides such as Nedd8 controls cellular functions including protein degradation, the cell cycle and transcription. Here we have used an activity-based chemical probe that covalently labels hydrolases. We identify four enzymes from Toxoplasma gondii mass spectrometry. The homologue mammalian UCHL3 was cloned both T. Plasmodium falciparum show possess deubiquitinating well deNeddylating activity. A phylogenetic...
Deubiquitinating enzymes function to cleave ubiquitin (Ub) moieties from modified proteins, serving maintain the pool of free Ub in cell while simultaneously impacting fate and a target protein. Like all eukaryotes, Plasmodium parasites rely on dynamic addition removal for their own growth survival. While humans possess around 100 deubiquitinases, contains ∼20 putative hydrolases, many which bear little no resemblance those other organisms. In this study, we characterize falciparum UBP-1,...
Ubiquitination is a post-translational modification implicated in variety of cellular functions, including transcriptional regulation, protein degradation and membrane trafficking. Ubiquitin the enzymes that act on it, although conserved essential eukaryotes, have not been well studied parasites, despite sequencing several parasite genomes. Several putative ubiquitin hydrolases identified Plasmodium falciparum based sequence homology alone, with no evidence expression or function. Here we...
Like their human hosts, Plasmodium falciparum parasites rely on the ubiquitin-proteasome system for survival. We previously identified PfUCHL3, a deubiquitinating enzyme, and here we characterize its activity changes in active site architecture upon binding to ubiquitin. find strong evidence that PfUCHL3 is essential parasite The crystal structures of both alone complex with ubiquitin-based suicide substrate UbVME suggest rather rigid crossover loop likely plays role restricting size...
The subcellular localization of the cluster differentiation 63 (CD63) tetraspanin and its interaction with class II MHC antigen presentation pathway were examined in context phagocytosis by live cell imaging, using monomeric red fluorescent protein-tagged mouse CD63 expressed primary bone marrow-derived cultures. Upon Cryptococcus neoformans polystyrene beads, was recruited selectively to C. neoformans-containing phagosomes a MyD88-independent acidification-dependent manner. Bead-containing...
Trichinella spiralis is a muscle-specific parasitic worm that uniquely intracellular. T. reprograms terminally differentiated skeletal muscle cells causing them to de-differentiate and re-enter the cell cycle, process cannot occur naturally in mammalian cells, but one holds great therapeutic potential. Although host ubiquitin pathway common target for viruses bacteria during infection, its role parasite pathogenesis has been largely overlooked. Here we demonstrate secreted proteins of...
Plasmodium parasites are the causative agents of malaria, a disease with wide public health repercussions. Increasing drug resistance and absence vaccine make finding new chemotherapeutic strategies imperative. Components ubiquitin ubiquitin-like pathways have garnered increased attention as novel targets given their necessity to parasite survival. Understanding how these regulated in identifying differences host is paramount selectively interfering parasites. Here, we focus on Nedd8...
ABSTRACT CD82 is a member of the tetraspanin superfamily, whose physiological role best described in context cancer metastasis. However, also associates with components class II major histocompatibility complex (MHC) antigen presentation pathway, including MHC molecules and peptide-loading machinery, as well CD63, another tetraspanin, suggesting for presentation. Here, we observe dynamic rearrangement after pathogen uptake by imaging CD82-mRFP1 expressed primary living dendritic cells....
The tetraspanin CD82 is a potent suppressor of tumor metastasis and regulates several processes including signal transduction, cell adhesion, motility, aggregation. However, the mechanisms by which participates in innate immunity are unknown. We report that key regulator TLR9 trafficking signaling. recognizes unmethylated cytosine-phosphate-guanine (CpG) motifs present viral, bacterial, fungal DNA. demonstrate associate macrophages, occurs endoplasmic reticulum (ER) post-ER. Moreover,...
The ubiquitin–proteasome system is essential to all eukaryotes and has been shown be critical parasite survival as well, including Plasmodium falciparum , the causative agent of deadliest form malarial disease. Despite central role pathway viability across its entire life-cycle, specific inhibitors targeting individual enzymes mediating ubiquitin attachment removal do not currently exist. ability disrupt P. growth at multiple developmental stages particularly attractive this could...
Ubiquitination is countered by a group of enzymes collectively called deubiquitinases (DUBs); ∼100 them can be found in the human genome. One most interesting aspects these ability some members to selectively recognize specific linkage types between ubiquitin polyubiquitin chains and their endo exo specificity. The structural basis exo-specific deubiquitination catalyzed DUB poorly understood. UCH37, cysteine conserved from fungi humans, proteasome-associated factor that regulates proteasome...
Trichinella spiralis is a zoonotic parasitic nematode that causes trichinellosis, disease has been identified on all continents except Antarctica. During chronic infection, T. larvae infect skeletal myofibres, severely disrupting their differentiation state.An activity-based probe, HA-Ub-VME, was used to identify deubiquitinating enzyme (DUB) activity in lysate of L1 larvae. Results were analysed by immuno-blot and immuno-precipitation, identifying number potential DUBs. Immuno-precipitated...
Malaria is a mosquito-borne infectious disease caused by unicellular eukaryotic parasites of the
Abstract The ubiquitin-proteasome system is essential to all eukaryotes and has been shown be critical parasite survival as well, including Plasmodium falciparum , the causative agent of deadliest form malarial disease. Despite central role pathway viability across its entire life-cycle, specific inhibitors targeting individual enzymes mediating ubiquitin attachment removal do not currently exist. ability disrupt P. growth at multiple developmental stages particularly attractive this could...
<title>Abstract</title> UCH37/UCHL5 is a conserved ubiquitin hydrolase with dual roles in proteasomal degradation and chromatin remodeling humans. Its Plasmodium falciparum ortholog, PfUCH37, essential for parasite viability possesses both DUB deneddylating activities. While PfUCH37 enriched proteasome preparations, its direct interaction broader functions remain unclear, particularly given the absence of INO80 homologs. This study utilizes transgenic parasites proteomics to identify...