TY - JOUR
T1 - Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β
AU - Cai, Xinjiang
AU - Srivastava, Shekhar
AU - Sun, Yi
AU - Li, Zhai
AU - Wu, Haiyan
AU - Zuvela-Jelaska, Ljiljana
AU - Li, Jun
AU - Salamon, Rachel S.
AU - Backer, Jonathan M.
AU - Skolnik, Edward Y.
PY - 2011/12/13
Y1 - 2011/12/13
N2 - 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.
AB - 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.
KW - Ca signaling
KW - Phosphatidylinositol-3 phosphate
KW - T helper cells
KW - Tripartite motif containing protein 27 knockout
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U2 - 10.1073/pnas.1111233109
DO - 10.1073/pnas.1111233109
M3 - Article
C2 - 22128329
AN - SCOPUS:84055187661
SN - 0027-8424
VL - 108
SP - 20072
EP - 20077
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 50
ER -