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Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation.

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.

Pubmed ID: 17137798

Authors

  • Oliver PM
  • Cao X
  • Worthen GS
  • Shi P
  • Briones N
  • MacLeod M
  • White J
  • Kirby P
  • Kappler J
  • Marrack P
  • Yang B

Journal

Immunity

Publication Data

December 18, 2006

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI-22295
  • Agency: NIAID NIH HHS, Id: AI-52225
  • Agency: NIDDK NIH HHS, Id: P50 DK052617-100007
  • Agency: NIDDK NIH HHS, Id: P50 DK52617
  • Agency: NHLBI NIH HHS, Id: R01 HL105834

Mesh Terms

  • Animals
  • Blotting, Western
  • Carrier Proteins
  • Cytokines
  • Flow Cytometry
  • Inflammation
  • Lymphocyte Activation
  • Membrane Proteins
  • Mice
  • Proto-Oncogene Proteins c-jun
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes
  • Th2 Cells
  • Ubiquitin-Protein Ligases