Abstract
Nedd4 family interacting protein-1 (Ndfip1) is a protein whose only known function is that it binds Nedd4, a HECT-type E3 ubiquitin ligase. Here we show that mice lacking Ndfip1 developed severe inflammation of the skin and lung and died prematurely. This condition was due to a defect in Ndfip1(-/-) T cells. Ndfip1(-/-) T cells were activated, and they proliferated and adopted a T helper 2 (Th2) phenotype more readily than did their Ndfip1(+/+) counterparts. This phenotype resembled that of Itchy mutant mice, suggesting that Ndfip1 might affect the function of Itch, an E3 ubiquitin ligase. We show that T cell activation promoted both Ndfip1 expression and its association with Itch. In the absence of Ndfip1, JunB half-life was prolonged after T cell activation. Thus, in the absence of Ndfip1, Itch is inactive and JunB accumulates. As a result, T cells produce Th2 cytokines and promote Th2-mediated inflammatory disease.
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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Animals
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism*
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Cytokines / biosynthesis
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Flow Cytometry
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Inflammation / genetics
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Inflammation / immunology*
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Intercellular Signaling Peptides and Proteins
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Lymphocyte Activation / immunology*
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mice
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Proto-Oncogene Proteins c-jun / immunology
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Proto-Oncogene Proteins c-jun / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Ubiquitin-Protein Ligases / immunology
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Carrier Proteins
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Cytokines
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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Ndfip1 protein, mouse
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Proto-Oncogene Proteins c-jun
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Itch protein, mouse
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Ubiquitin-Protein Ligases