Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells

• Published in: Nature communications 2016-04, Vol.7 (1), p.11226-11226, Article 11226
• Main Authors: O’Leary, Claire E., Riling, Christopher R., Spruce, Lynn A., Ding, Hua, Kumar, Suresh, Deng, Guoping, Liu, Yuhong, Seeholzer, Steven H., Oliver, Paula M.
• Format: Article
• Language: English
• Subjects: 631/250/127; 631/250/1619/554/1898; 631/337/475; 631/45/612/1222; 82; 82/58; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - metabolism; Cell division; Cell Proliferation; Cells, Cultured; Colitis - genetics; Colitis - metabolism; Cytokines; Cytokines - metabolism; Female; Humanities and Social Sciences; Immunoblotting; Janus Kinase 1 - metabolism; Lymphocyte Count; Lymphocytes; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; multidisciplinary; Pathology; Proteins; Proteolysis; Proteomics - methods; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); Signal Transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11226

Nedd4 family E3 ubiquitin ligases have been shown to restrict T-cell function and impact T-cell differentiation. We show here that Ndfip1 and Ndfip2, activators of Nedd4 family ligases, together limit accumulation and function of effector CD4+ T cells. Using a three-part proteomics approach in primary T cells, we identify stabilization of Jak1 in Ndfip1/2-deficient T cells stimulated through the TCR. Jak1 degradation is aborted in activated T cells that lack Ndfips. In wild-type cells, Jak1 degradation lessens CD4+ cell sensitivity to cytokines during TCR stimulation, while in Ndfip-deficient cells cytokine responsiveness persists, promoting increased expansion and survival of pathogenic effector T cells. Thus, Ndfip1/Ndfip2 regulate the cross talk between the T-cell receptor and cytokine signalling pathways to limit inappropriate T-cell responses. Ndfip1 is an activator of Itch E3 ubiquitin ligase that limits T cell activation. Here the authors identify Jak1 in a proteomic screen for Ndfip dependent substrates, and show that Ndfip1/2 double-deficient T cells have reduced degradation of Jak1 and as a result are hyper-responsive to cytokine stimulation.