Single-cell transcriptomic analysis of tumor-infiltrated immune cells from myeloid-specific Usp18 knockout mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE173705 | GEO | 2024/02/14
REPOSITORIES: GEO
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Project description:The deubiquitylating enzyme USP18 is a major negative regulator of the interferon (IFN) signalling cascade. IFN pathways contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy and are often upregulated in certain tumours, including breast, lung, and colon tumours. USP18 is the predominant human protease that cleaves interferon-stimulated gene ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. In this study, using advanced proteomic techniques, we have expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line (HAP1) treated with type I IFN. Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. Our results suggest USP18 as a pharmacological target in cancer immunotherapy and radiotherapy.
2022-02-15 | PXD018299 | Pride
Project description:Single-cell transcriptomic analysis of tumor-infiltrated immune cells from myeloid-specific Usp18 knockout mice
| PRJNA726807 | ENA
Project description:Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating interferon-induced ubiquitin-like (Ubl) modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) capable of selectively detecting USP18 activity over other ISG15 cross-reactive Ubl proteases by incorporating unnatural amino acids into the C-terminal tail of ISG15. Combining with a ubiquitin-based DUB ABP, the selective USP18 ABP is employed in a chemoprotemic platform to identify and assess inhibitors of DUBs including USP18. We further demonstrate that USP18 ABPs can be utilized to profile differential activities of USP18 in lung cancer cell lines, providing a strategy that will help define the activity-related landscape of USP18 in different disease states and unravel important (de)ISGylation-dependent biological processes.
2024-03-26 | MSV000094406 | MassIVE
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Brain lysate of adult WT, USP18ko, IFNAR1ko and USP18ko:IFNARko mice were analyzed
2015-04-20 | E-GEOD-61499 | biostudies-arrayexpress
Project description:USP18 is an interferon type 1 (IFN-1) induced gene that negatively regulates the IFN-1 signalling pathway, which plays a role in many immune related pathologies. Dermatomyositis (DM) is characterised by excessive IFN-1 immune response and muscle degeneration. We found USP18 to be expressed in DM myofibers suggesting a role in muscle cell biology. USP18 depletion induced muscle cell differentiation under nutrient-rich conditions independent of IFN-1 signalling. Downregulation of cell cycle gene network and sarcomeric protein networks, and dysregulation of myogenic (co-)transcription regulators were found in USP18-depleted differentiated cells. Sarcomeric integrity of USP18-depleted cells deteriorated during muscle cell maturation. Our results revealed USP18 as a critical regulator at the intersection between proliferation and differentiation as well as during the maturation of muscle cells. We suggest that a USP18 IFN-1-independent pathway may contribute to muscle regeneration in muscle pathologies.
2023-05-10 | PXD032406 | Pride
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Primary microglia (WT, USP18ko and USP18_C61A mice) and BV-2 cells (treated with control siRNA or siRNA against USP18) were incubated with 500 U/ml IFN-b. At different timepoints (0h, 6h, and 24h) RNA samples were taken and analyzed via Microarray
2015-04-20 | E-GEOD-61500 | biostudies-arrayexpress
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS.
2015-04-20 | GSE61499 | GEO
Project description:USP18 is an interferon type 1 (IFN-1) induced gene that negatively regulates the IFN-1 signalling pathway, which plays a role in many immune related pathologies. Dermatomyositis (DM) is characterised by excessive IFN-1 immune response and muscle degeneration. We found USP18 to be expressed in DM myofibers suggesting a role in muscle cell biology. USP18 depletion induced muscle cell differentiation under nutrient-rich conditions independent of IFN-1 signalling. Downregulation of cell cycle gene network and sarcomeric protein networks, and dysregulation of myogenic (co-)transcription regulators were found in USP18-depleted differentiated cells. Sarcomeric integrity of USP18-depleted cells deteriorated during muscle cell maturation. Our results revealed USP18 as a critical regulator at the intersection between proliferation and differentiation as well as during the maturation of muscle cells. We suggest that a USP18 IFN-1-independent pathway may contribute to muscle regeneration in muscle pathologies.
2022-03-23 | GSE198794 | GEO
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS.
2015-04-20 | GSE61500 | GEO
Project description:Usp18 is a potent negative reguator of type I IFN signaling. However, it is not well characterized how Usp18 affects IFN stimulated genes (ISGs) induction in AML in mouse model. Here, we analyzed the transcriptomic data when combined with heterozygous depletion of USP18, which phenotypicaly reduce AE9a leukemia progression.
2022-11-09 | GSE165424 | GEO