Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

Xinjiang Cai, Shekhar Srivastava, Yi Sun, Zhai Li, Haiyan Wu, Ljiljana Zuvela-Jelaska, Jun Li, Rachel S. Salamon, Jonathan M. Backer, Edward Y. Skolnik

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20072-20077
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number50
DOIs
StatePublished - Dec 13 2011

Keywords

  • Ca signaling
  • Phosphatidylinositol-3 phosphate
  • T helper cells
  • Tripartite motif containing protein 27 knockout

ASJC Scopus subject areas

  • General

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