title: Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β.
abstract: The K(+) channel KCa3.1 is required for Ca(2+) influx and the subsequent activation of CD4 T cells. The class II phosphatidylinositol 3 kinase C2β (PI3KC2β) is activated by the T-cell receptor (TCR) and is critical for KCa3.1 channel activation. Tripartite motif containing protein 27 (TRIM27) is a member of a large family of proteins that function as Really Interesting New Gene (RING) E3 ubiquitin ligases. We now show that TRIM27 functions as an E3 ligase and mediates lysine 48 polyubiquitination of PI3KC2β, leading to a decrease in PI3K enzyme activity. By inhibiting PI3KC2β, TRIM27 also functions to negatively regulate CD4 T cells by inhibiting KCa3.1 channel activity and TCR-stimulated Ca(2+) influx and cytokine production in Jurkat, primary human CD4 T cells, and Th0, Th1, and Th2 CD4 T cells generated from TRIM27(-/-) mice. These findings provide a unique mechanism for regulating class II PI3Ks, and identify TRIM27 as a previously undescribed negative regulator of CD4 T cells.
authors: Division of Nephrology, New York University Langone Medical Center, The Helen L and Martin S Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York, NY 10016, USA.
authors: Xinjiang
authors: X
authors: Cai
authors: Shekhar
authors: S
authors: Srivastava
authors: Yi
authors: Y
authors: Sun
authors: Zhai
authors: Z
authors: Li
authors: Haiyan
authors: H
authors: Wu
authors: Ljiljana
authors: L
authors: Zuvela-Jelaska
authors: Jun
authors: J
authors: Li
authors: Rachel S
authors: RS
authors: Salamon
authors: Jonathan M
authors: JM
authors: Backer
authors: Edward Y
authors: EY
authors: Skolnik
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D015640:Ion Channel Gating; D019169:Jurkat Cells; D051379:Mice; D009088:Mucoproteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D000070584:Tripartite Motif Proteins
chemical_list: D002118:Calcium; D016207:Cytokines; D004268:DNA-Binding Proteins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D009088:Mucoproteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025821:Polyubiquitin; D011948:Receptors, Antigen, T-Cell; D044767:Ubiquitin-Protein Ligases; C496923:KCNN4 protein, human; C496925:Kcnn4 protein, mouse; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins; C010393:lysin, gastropoda; C489296:Trim27 protein, mouse