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

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.

• Authors: Paula M Oliver, Xiao Cao, George Scott Worthen, Peijun Shi, Natalie Briones, Megan MacLeod, Janice White, Patricia Kirby, John Kappler, Philippa Marrack, Baoli Yang
• Journal: Immunity (Immunity) Vol. 25 Issue 6 Pg. 929-40 (Dec 2006) ISSN: 1074-7613 [Print] United States
• PMID: 17137798 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cytokines
• Intercellular Signaling Peptides and Proteins
• Membrane Proteins
• Ndfip1 protein, mouse
• Proto-Oncogene Proteins c-jun
• Itch protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Animals
• Blotting, Western
• Carrier Proteins (genetics, immunology, metabolism)
• Cytokines (biosynthesis)
• Flow Cytometry
• Inflammation (genetics, immunology)
• Intercellular Signaling Peptides and Proteins
• Lymphocyte Activation (immunology)
• Membrane Proteins (genetics, immunology, metabolism)
• Mice
• Proto-Oncogene Proteins c-jun (immunology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes (immunology, metabolism)
• Th2 Cells (immunology, metabolism)
• Ubiquitin-Protein Ligases (immunology, metabolism)