Abstract
Repeated injection of alpha-galactosylceramide, an agonistic ligand for natural killer T (NKT) cells, results in long-term unresponsiveness or anergy, which severely limits its clinical application. However, the molecular mechanisms leading to NKT anergy induction remain unclear. We show here that the decreased IFN-gamma production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency. Cbl-b E3 ligase activity is critical for the anergy induction, as revealed by the similarity between Cbl-b(-/-) and its RING finger mutant NKT cells. Cbl-b binds and promotes monoubiquitination to CARMA1, a critical signaling molecule in NFkappaB activation. Ubiquitin conjugation to CARMA1 disrupts its complex formation with Bcl10 without affecting its protein stability. In addition, CARMA1(-/-) NKT cells are defective in IFN-gamma production. The study identifies an important signaling pathway linking Cbl-b-induced monoubiquitination to NFkappaB activation in NKT cell anergy induction, which may help design approaches for human cancer therapy.
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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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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CARD Signaling Adaptor Proteins / deficiency
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism*
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Clonal Anergy*
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Galactosylceramides / immunology
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Humans
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Melanoma, Experimental / immunology
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / secondary
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Mutant Strains
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NF-kappa B / metabolism
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Natural Killer T-Cells / immunology*
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Natural Killer T-Cells / metabolism*
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Proto-Oncogene Proteins c-cbl / deficiency
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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Signal Transduction / immunology
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Ubiquitination
Substances
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Adaptor Proteins, Signal Transducing
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CARD Signaling Adaptor Proteins
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Card11 protein, mouse
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Cblb protein, mouse
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Galactosylceramides
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NF-kappa B
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alpha-galactosylceramide
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Proto-Oncogene Proteins c-cbl
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Cbl protein, mouse