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. © 2006 Elsevier Inc. All rights reserved.
Oliver, P. M., Cao, X., Worthen, G. S., Shi, P., Briones, N., MacLeod, M., … Yang, B. (2006). Ndfip1 Protein Promotes the Function of Itch Ubiquitin Ligase to Prevent T Cell Activation and T Helper 2 Cell-Mediated Inflammation. Immunity, 25(6), 929–940. https://doi.org/10.1016/j.immuni.2006.10.012