Abstract
Sustained elevation of intracellular calcium by Ca2+ release–activated Ca2+ channels is required for lymphocyte activation. Sustained Ca2+ entry requires endoplasmic reticulum (ER) Ca2+ depletion and prolonged activation of inositol 1,4,5-trisphosphate receptor (IP3R)/Ca2+ release channels. However, a major isoform in lymphocyte ER, IP3R1, is inhibited by elevated levels of cytosolic Ca2+, and the mechanism that enables the prolonged activation of IP3R1 required for lymphocyte activation is unclear. We show that IP3R1 binds to the scaffolding protein linker of activated T cells and colocalizes with the T cell receptor during activation, resulting in persistent phosphorylation of IP3R1 at Tyr353. This phosphorylation increases the sensitivity of the channel to activation by IP3 and renders the channel less sensitive to Ca2+-induced inactivation. Expression of a mutant IP3R1-Y353F channel in lymphocytes causes defective Ca2+ signaling and decreased nuclear factor of activated T cells activation. Thus, tyrosine phosphorylation of IP3R1-Y353 may have an important function in maintaining elevated cytosolic Ca2+ levels during lymphocyte activation.
Highlights
T cell activation is initiated by the engagement of the antigen/ major histocompatibility complex with the T cell receptor (TCR), triggering the formation of the immunological synapse (Yokosuka et al, 2005)
We wanted to examine if phosphorylation at Y353 altered the ability of IP3R1 to cocap with the TCR upon T cell activation
Upon T cell activation, both TCR/CD3 and IP3R1 phosphoY353 showed a dramatic colocalization to one site in the cell, forming a tight cluster at the site of stimulation (Fig. 1 A)
Summary
T cell activation is initiated by the engagement of the antigen/ major histocompatibility complex with the T cell receptor (TCR), triggering the formation of the immunological synapse (Yokosuka et al, 2005). The immunological synapse is a dynamic, highly ordered structure that includes adaptor proteins and kinases, including the nonreceptor Src tyrosine kinases Lck and Fyn (Monks et al, 1998; Bromley et al, 2001). Once activated, these kinases trigger a phosphorylation cascade that leads to the activation of PLCγ-1, which hydrolyzes phosphotidylinositol 4,5 bisphosphate into diacylglycerol and inositol 1,4,5-trisphosphate (IP3; Koretzky and Myung, 2001). IP3 triggers Ca2+ release from the ER by activating the IP3 receptor (IP3R; Berridge and Irvine, 1984). ER Ca2+ depletion triggers the redistribution of STIM1 such that ER Ca2+ depletion is sensed by stromal interaction molecule 1 (STIM1), an EF hand containing ER transmembrane protein (Liou et al, 2005; Roos et al, 2005).
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