Abstract
Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Apoptosis / immunology
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Cell Differentiation / immunology
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Cell Line, Tumor
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Cell Survival
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HCT116 Cells
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Humans
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Leupeptins / pharmacology
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Listeria monocytogenes / immunology
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Listeriosis / immunology
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Lymphocyte Activation / immunology
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Melanoma, Experimental / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NFATC Transcription Factors / metabolism*
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / immunology*
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Th1 Cells / immunology*
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Tumor Escape
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Tumor Suppressor Protein p53 / immunology
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Ubiquitin-Specific Proteases / genetics
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Ubiquitin-Specific Proteases / immunology*
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Ubiquitination / genetics
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Ubiquitination / immunology
Substances
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Leupeptins
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NFATC Transcription Factors
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Nfatc2 protein, mouse
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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USP15 protein, human
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Ubiquitin-Specific Proteases
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde