Proc Natl Acad Sci 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.
Srivastava S, Zhdanova O, Di L, Li Z, Albaqumi M, Wulff H, Skolnik EY.
Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
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 finding 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 Ca(2+) signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca(2+) 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 Ca(2+) 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
