Ed Skolnik and colleagues identify new signaling pathway critical for negative regulation of T and B cells
Proceedings of the National Academy of Sciences of the U.S.A. 2008 Sep 23;105(38):14442-6. Epub 2008 Sep 16.
Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1
Shekhar Srivastava, Olga Zhdanova, Lie Di, Zhai Li, Mamdouh Albaqumi, Heike Wulff, and Edward Y. Skolnik
Significance:
Negative regulators of T and B cells are critical to both set a minimal threshold for T cell activation as well as to provide negative feedback to limit T cell activation. The important role for these molecules in attenuating T and B cell responses is evident by the finding that many negative regulators of T and B signaling are required to prevent the development of autoimmune diseases. The findings presented in this paper identify for the first time a new signaling pathway that is critical for the negative regulation of T and B cells and suggests that dysregulation of this signaling pathway may predispose a subset of patients to autoimmune diseases.
Abstract:
The calcium activated K+ channel KCa3.1 plays an important role in T lymphocyte Ca2+ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca2+ influx.We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, is required for KCa3.1 channel activation in human CD4 T lymphocytes. We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1. Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity. Decreased expression of PHPT-1 by siRNA in human CD4 T cells resulted in an increase in KCa3.1 channel activity and increased Ca2+ influx and proliferation after T cell receptor (TCR) activation, indicating that endogenous PHPT-1 functions to negatively regulate CD4 T cells.
Our findings provide a previously unrecognized example of a mammalian histidine phosphatase negatively regulating TCR signaling and are one of the few examples of histidine phosphorylation/dephosphorylation influencing a biological process in mammals.
PMID: 18796614