A5020726418- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- interferon and immune responses
- Protein Degradation and Inhibitors
- Autophagy in Disease and Therapy
- Histone Deacetylase Inhibitors Research
- Muscle Physiology and Disorders
- Cellular transport and secretion
- Click Chemistry and Applications
- Immunotherapy and Immune Responses
- Cancer-related Molecular Pathways
- Mitochondrial Function and Pathology
- Genetic Neurodegenerative Diseases
- Endoplasmic Reticulum Stress and Disease
- Protein Kinase Regulation and GTPase Signaling
- Ferroptosis and cancer prognosis
- Peroxisome Proliferator-Activated Receptors
- Cancer, Hypoxia, and Metabolism
- Sphingolipid Metabolism and Signaling
- Meat and Animal Product Quality
- Reproductive Biology and Fertility
- Adipose Tissue and Metabolism
- Cytokine Signaling Pathways and Interactions
- Cell death mechanisms and regulation
- Chronic Myeloid Leukemia Treatments
University of Oxford
2016-2025
Chinese Academy of Medical Sciences & Peking Union Medical College
2020-2025
Academy of Medical Sciences
2020-2025
Discovery Institute
2018-2024
Science Oxford
2022-2024
Target (United States)
2018-2021
Rockefeller University
2021
Rockefeller University Press
2021
Directorate-General Joint Research Centre
2020
Consejo Superior de Investigaciones Científicas
2017
The mitochondrial deubiquitylase USP30 negatively regulates the selective autophagy of damaged mitochondria. We present characterisation an N-cyano pyrrolidine compound, FT3967385, with high selectivity for USP30. demonstrate that ubiquitylation TOM20, a component outer membrane import machinery, represents robust biomarker both loss and inhibition. A proteomics analysis, on SHSY5Y neuroblastoma cell line model, directly compares effects genetic chemical have thereby identified subset events...
Certain inhibitor of apoptosis (IAP) family members are sentinel proteins that prevent untimely cell death by inhibiting caspases. Antagonists, including second mitochondria-derived activator caspases (SMAC), regulate IAPs and drive death. Baculoviral IAP repeat-containing protein 6 (BIRC6), a giant with dual E2 E3 ubiquitin ligase activity, regulates programmed through unknown mechanisms. We show BIRC6 directly restricts executioner caspase-3 -7 ubiquitinates caspase-3, -7, -9, working...
Inhibition of the mitochondrial deubiquitinating (DUB) enzyme USP30 is neuroprotective and presents therapeutic opportunities for treatment idiopathic Parkinson's disease mitophagy-related disorders. We integrated structural quantitative proteomics with biochemical assays to decipher mode action covalent inhibition by a small-molecule containing cyanopyrrolidine reactive group, USP30-I-1. The inhibitor demonstrated high potency selectivity endogenous in neuroblastoma cells. Enzyme kinetics...
Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count hearing defects. also exports S1P-mimicking FTY720-P (Fingolimod) thereby central pharmacokinetics of this drug when treating multiple sclerosis. Here, we use combination cryo-electron microscopy, immunofluorescence, vitro binding vivo export assays, molecular dynamics simulations probe...
Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative disorders such Parkinson's Disease. USP30 inhibition may counteract deleterious effects impaired turnover damaged mitochondria, which is inherent to both familial and sporadic forms disease. Small-molecule inhibitors targeting are currently in development, but little known about their precise nature...
Dysregulation of the ubiquitin-proteasome systems is a hallmark various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), deubiquitinating enzyme, expressed primarily in central nervous system under normal physiological conditions, however, considered an oncogene cancers, melanoma, lung, breast, lymphoma. Thus, UCHL1 inhibitors could serve as viable treatment strategy against these aggressive cancers. Herein, we describe covalent...
Enzymes that bind and process ubiquitin, a small 76 amino acid protein, have been recognized as pharmacological targets in oncology, immunological disorders neurodegeneration. Mass spectrometry technology has now reached the capacity to cover proteome with enough depth interrogate entire biochemical pathways including those contain DUBs E3 ligase substrates. We recently characterized breast cancer cell (MCF7) deep by detecting quantifying ~10,000 proteins, within this data set, we can detect...
OTULIN (OTU Deubiquitinase With Linear Linkage Specificity) specifically hydrolyzes methionine1 (Met1)-linked ubiquitin chains conjugated by LUBAC (linear chain assembly complex). Here we report on the mass spectrometric identification of interactor SNX27 (sorting nexin 27), an adaptor endosomal retromer complex responsible for protein recycling to cell surface. The C-terminal PDZ-binding motif (PDZbm) in associates with cargo-binding site PDZ domain SNX27. By solving structure OTU domain,...
Abstract Background Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance conventional chemotherapy, radiotherapy, and immunotherapy, are often deregulated in cancer. The deubiquitylating enzyme USP18 is major negative regulator IFN cascade predominant human protease that cleaves ISG15, ubiquitin-like protein tightly regulated context immunity, from its modified substrate proteins vivo. Methods In this study, using advanced proteomic...
Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient's 5-year survival rate less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization the oncoproteins c-MYC, c-JUN, Δp63. Here, we show that genetic inactivation Usp28-induced regression established murine LSCC lung tumours. We developed small molecule inhibits USP28...
When a ribosome stalls during translation, it runs the risk of collision with trailing ribosome. Such an encounter leads to formation stable di-ribosome complex, which needs be resolved by dedicated machinery. The initial stalling and subsequent resolution di-ribosomal complexes requires activity Makorin ZNF598 ubiquitin E3 ligases, respectively, through ubiquitylation eS10 uS10 subunits We have developed specific small-molecule inhibitor deubiquitylase USP9X. Proteomics analysis, following...
Deubiquitinating enzymes (DUBs) are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 two structurally related USP14/UCH-37 inhibitors. Through proteomic approach, we demonstrate that these compounds diverse range of proteins, resulting in the formation higher molecular weight (MW) complexes. Activity-based proteome profiling identified CIAPIN1 as submicromolar covalent VLX1570, further analysis demonstrated high MW complex leads...
Abstract Cancer remains one of the leading causes mortality worldwide, to increased interest in utilizing immunotherapy strategies for better cancer treatments. In past decade, CD103 + T cells have been associated with clinical prognosis patients cancer. However, specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired at synaptic microclusters cells. colocalization cell...
RIG-I-like receptors (RLRs) are cytoplasmic RNA sensors that promote type I and III interferon (IFN) production in response to ligands of viral or endogenous origin. The RLR pathway is tightly regulated by dynamic post-translational modifications, including ubiquitination. Huwe1 a HECT domain-containing giant ubiquitin E3 ligase has not been implicated the IFN pathway. Here, we investigated whether required for induction downstream RLRs. We demonstrate loss severely attenuates expression...
ABSTRACT Deubiquitinating enzymes (DUBs) are pivotal regulators of ubiquitination, a vital post-translational modification essential for cellular processes. Dysregulated DUB activity disrupts homeostasis, driving diseases like cancer and neurodegeneration. Ubiquitin-specific protease 32 (USP32) has emerged as promising therapeutic target due to its role in endosomal autophagosomal dynamics association with breast, ovarian, lung cancers. Here, we describe Huib32 ( H uman de U biquitinase Inhi...
The methionine 1 (M1)-specific deubiquitinase (DUB) OTULIN acts as a negative regulator of nuclear factor κB signaling and immune homeostasis. By replacing Gly76 in distal ubiquitin (Ub) by dehydroalanine we designed the diubiquitin (diUb) activity-based probe UbG76Dha-Ub (OTULIN [ABP]) that couples to catalytic site thereby captures its active conformation. ABP displays high selectivity for does not label other M1-cleaving DUBs, including CYLD. only detectable cross-reactivities were...
Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for existence of other cross-reactive proteases, these remain be identified. Here, we identify deubiquitinase USP16 as an means activity-based profiling. Recombinant cleaved pro-ISG15 isopeptide-linked model substrates in vitro, well ISGylated from cell...
Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, inhibits receptor activity through scaffold role.
The ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum survival and represents a potential target antimalarial therapies. We utilised ubiquitin- activity based probe (Ub-Dha) to capture active components of the ubiquitin conjugating machinery during asexual blood-stage development. Several E2 ubiquitin-conjugating enzymes, E1 activating enzyme, HECT E3 ligase PfHEUL were identified validated through in vitro ubiquitination assays. also demonstrate selective functional...