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Nature Communications Oct 2023Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce degradation by the ubiquitin-proteasome system (UPS) offer new...
Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce degradation by the ubiquitin-proteasome system (UPS) offer new opportunities to engage targets that remain challenging to be inhibited by conventional small molecules. One fundamental element in the degradation process is the E3 ligase. However, less than 2% amongst hundreds of E3 ligases in the human genome have been engaged in current studies in the TPD field, calling for the recruiting of additional ones to further enhance the therapeutic potential of TPD. To accelerate the development of PROTACs utilizing under-explored E3 ligases, we systematically characterize E3 ligases from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, and PPI interface by analyzing 30 large-scale data sets. Our analysis uncovers several E3 ligases as promising extant PROTACs. In total, combining confidence score, ligandability, expression pattern, and PPI, we identified 76 E3 ligases as PROTAC-interacting candidates. We develop a user-friendly and flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers to rapidly identify E3 ligases with promising TPD activities against specifically desired targets, facilitating the development of these therapies in cancer and beyond.
Topics: Humans; Ubiquitin-Protein Ligases; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitination; Neoplasms
PubMed: 37845222
DOI: 10.1038/s41467-023-42233-2 -
Nature Reviews. Drug Discovery Feb 2024Targeted protein degradation (TPD) has emerged in the past decade as a major new drug modality to remove intracellular proteins with bispecific small molecules that... (Review)
Review
Targeted protein degradation (TPD) has emerged in the past decade as a major new drug modality to remove intracellular proteins with bispecific small molecules that recruit the protein of interest (POI) to an E3 ligase for degradation in the proteasome. Unlike classic occupancy-based drugs, intracellular TPD (iTPD) eliminates the target and works catalytically, and so can be more effective and sustained, with lower dose requirements. Recently, this approach has been expanded to the extracellular proteome, including both secreted and membrane proteins. Extracellular targeted protein degradation (eTPD) uses bispecific antibodies, conjugates or small molecules to degrade extracellular POIs by trafficking them to the lysosome for degradation. Here, we focus on recent advances in eTPD, covering degrader systems, targets, molecular designs and parameters to advance them. Now almost any protein, intracellular or extracellular, is addressable in principle with TPD.
Topics: Humans; Proteolysis; Proteasome Endopeptidase Complex; Membrane Proteins; Drug Discovery; Ubiquitin-Protein Ligases
PubMed: 38062152
DOI: 10.1038/s41573-023-00833-z -
Nature Metabolism Oct 2023Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we...
Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we identify the glycolytic enzyme enolase 2 (ENO2) as a driver of resistance to antiangiogenic therapy in colorectal cancer (CRC) mouse models and human participants. ENO2 overexpression induces neuroendocrine differentiation, promotes malignant behaviour in CRC and desensitizes CRC to antiangiogenic drugs. Mechanistically, the ENO2-derived metabolite phosphoenolpyruvate (PEP) selectively inhibits histone deacetylase 1 (HDAC1) activity, which increases the acetylation of β-catenin and activates the β-catenin pathway in CRC. Inhibition of ENO2 with enolase inhibitors AP-III-a4 or POMHEX synergizes the efficacy of antiangiogenic drugs in vitro and in mice bearing drug-resistant CRC xenograft tumours. Together, our findings reveal that ENO2 constitutes a useful predictive biomarker and therapeutic target for resistance to antiangiogenic therapy in CRC, and uncover a previously undefined and metabolism-independent role of PEP in regulating resistance to antiangiogenic therapy by functioning as an endogenous HDAC1 inhibitor.
Topics: Humans; Animals; Mice; beta Catenin; Phosphoenolpyruvate; Histone Deacetylase 1; Phosphopyruvate Hydratase
PubMed: 37667133
DOI: 10.1038/s42255-023-00883-y -
Seminars in Immunology Nov 2023Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive... (Review)
Review
Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.
Topics: Humans; Aged; Proteostasis; T-Cell Senescence; Aging; Proteasome Endopeptidase Complex; Autophagy
PubMed: 37708826
DOI: 10.1016/j.smim.2023.101838 -
Science (New York, N.Y.) Aug 2023Aubiquitin-independent pathway targets nuclear proteins to the proteasome.
Aubiquitin-independent pathway targets nuclear proteins to the proteasome.
Topics: Cytoplasm; Nuclear Proteins; Proteasome Endopeptidase Complex; Proteolysis; Genes, Immediate-Early; Humans; Animals; Mice
PubMed: 37616357
DOI: 10.1126/science.adj8230 -
European Journal of Immunology Apr 2024Immunoproteasomes are a special class of proteasomes, which can be induced with IFN-γ in an inflammatory environment. In recent years, it became evident that certain...
Immunoproteasomes are a special class of proteasomes, which can be induced with IFN-γ in an inflammatory environment. In recent years, it became evident that certain immune cell types constitutively express high levels of immunoproteasomes. However, information regarding the basal expression of proteolytically active immunoproteasome subunits in different types of immune cells is still rare. Hence, we quantified standard proteasome subunits (β1c, β2c, β5c) and immunoproteasome subunits (LMP2, MECL-1, LMP7) in the major murine (CD4 T cells, CD8 T cells, CD19 B cells, CD11c dendritic cells, CD49d natural killer cells, Ly-6G neutrophils) and human immune cell (CD4 T cells, CD8 T cells, CD19 B cells, CD1cCD141 myeloid dendritic cells, CD56 natural killer cells, granulocytes) subsets. The different human immune cell types were isolated from peripheral blood and the murine immune cell subsets from spleen. We found that proteasomes of most immune cell subsets mainly consist of immunoproteasome subunits. Our data will serve as a reference and guideline for immunoproteasome expression and imply a special role of immunoproteasomes in immune cells.
Topics: Animals; Mice; Humans; Proteasome Endopeptidase Complex; CD8-Positive T-Lymphocytes
PubMed: 38458995
DOI: 10.1002/eji.202350613 -
Neuromolecular Medicine Dec 2023Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and... (Review)
Review
Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.
Topics: Humans; Aged; Middle Aged; Parkinson Disease; Proteasome Endopeptidase Complex; Ubiquitin; Neurodegenerative Diseases; Mitophagy; Ubiquitin-Protein Ligases
PubMed: 37698835
DOI: 10.1007/s12017-023-08755-0 -
International Journal of Molecular... Aug 2023The involvement of prostaglandins in cancer was first observed in human esophageal carcinoma cells, whose invasive and metastatic potential in nude mice was found to be...
The involvement of prostaglandins in cancer was first observed in human esophageal carcinoma cells, whose invasive and metastatic potential in nude mice was found to be related to PGE and PGF production [...].
Topics: Animals; Mice; Humans; Mice, Nude; Prostaglandins; Dinoprostone; Cyclooxygenase 2; Cyclooxygenase 1; Esophageal Neoplasms
PubMed: 37569718
DOI: 10.3390/ijms241512342 -
The Plant Journal : For Cell and... May 2024CpcL-phycobilisomes (CpcL-PBSs) are a reduced type of phycobilisome (PBS) found in several cyanobacteria. They lack the traditional PBS terminal energy emitters, but...
CpcL-phycobilisomes (CpcL-PBSs) are a reduced type of phycobilisome (PBS) found in several cyanobacteria. They lack the traditional PBS terminal energy emitters, but still show the characteristic red-shifted fluorescence at ~670 nm. We established a method of assembling in vitro a rod-membrane linker protein, CpcL, with phycocyanin, generating complexes with the red-shifted spectral features of CpcL-PBSs. The red-shift arises from the interaction of a conserved key glutamine, Q57 of CpcL in Synechocystis sp. PCC 6803, with a single phycocyanobilin chromophore of trimeric phycocyanin at one of the three β82-sites. This chromophore is the terminal energy acceptor of CpcL-PBSs and donor to the photosystem(s). This mechanism also operates in PBSs from Acaryochloris marina MBIC11017. We then generated multichromic complexes harvesting light over nearly the complete visible range via the replacement of phycocyanobilin chromophores at sites α84 and β153 of phycocyanins by phycoerythrobilin and/or phycourobilin. The results demonstrate the rational design of biliprotein-based light-harvesting elements by engineering CpcL and phycocyanins, which broadens the light-harvesting range and accordingly improves the light-harvesting capacity and may be potentially applied in solar energy harvesting.
Topics: Phycobilisomes; Phycocyanin; Synechocystis; Bacterial Proteins; Phycobilins; Cyanobacteria
PubMed: 38319793
DOI: 10.1111/tpj.16666 -
Nanoscale Feb 2024PROteolysis TArgeting Chimeras (PROTACs), as a recently identified technique in the field of new drug development, provide new concepts for disease treatment and are... (Review)
Review
PROteolysis TArgeting Chimeras (PROTACs), as a recently identified technique in the field of new drug development, provide new concepts for disease treatment and are expected to revolutionize drug discovery. With high specificity and flexibility, PROTACs serve as an innovative research tool to target and degrade disease-relevant proteins that are not currently pharmaceutically vulnerable to eliminating their functions by hijacking the ubiquitin-proteasome system. To date, PROTACs still face the challenges of low solubility, poor permeability, off-target effects, and metabolic instability. The combination of nanotechnology and PROTACs has been explored to enhance the performance of PROTACs regarding overcoming these challenging hurdles. In this review, we summarize the latest advancements in the building-block design of PROTAC prodrug nanoparticles and provide an overview of existing/potential delivery systems and loading approaches for PROTAC drugs. Furthermore, we discuss the current status and prospects of the split-and-mix approach for PROTAC drug optimization. Additionally, the advantages and translational potentials of carrier-free nano-PROTACs and their combinational therapeutic effects are highlighted. This review aims to foster a deeper understanding of this rapidly evolving field and facilitate the progress of nano-PROTACs that will continue to push the boundaries of achieving selectivity and controlled release of PROTAC drugs.
Topics: Proteolysis; Proteolysis Targeting Chimera; Proteasome Endopeptidase Complex; Proteins; Drug Discovery
PubMed: 38305466
DOI: 10.1039/d3nr06059d