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Calcium-induced T Lymphocyte Apoptosis

Calcium (Ca2+) plays a major role in life and death in T-Cells. Elevation of intracellular free Ca2+ is one of the key triggering signals for T-Cell activation by antigen. The binding of antigen-MHC Class-II complex on antigen presenting cells (APC) to the TCR-CD3 complex on T-cells triggers the recruitment of several tyrosine kinases and substrates to the TCR/CD3/CD4 complex, ultimately resulting in the phosphorylation and activation of PLC-γ1. PLC-γ1 cleaves PIP2 in the plasma membrane to generate DAG and IP3, which activate PKC and cause accumulation of free Ca2+ in the cytosol respectively. Intracellular free Ca2+ can come from two sources: the endoplasmic reticulum and the extracellular space...

Calcium-induced T Lymphocyte Apoptosis

Pathway Summary

Calcium (Ca2+) plays a major role in life and death in T-Cells. Elevation of intracellular free Ca2+ is one of the key triggering signals for T-Cell activation by antigen. The binding of antigen-MHC Class-II complex on antigen presenting cells (APC) to the TCR-CD3 complex on T-cells triggers the recruitment of several tyrosine kinases and substrates to the TCR/CD3/CD4 complex, ultimately resulting in the phosphorylation and activation of PLC-γ1. PLC-γ1 cleaves PIP2 in the plasma membrane to generate DAG and IP3, which activate PKC and cause accumulation of free Ca2+ in the cytosol respectively. Intracellular free Ca2+ can come from two sources: the endoplasmic reticulum and the extracellular space. The activity of the IP3R/ITPR is increased during the early phase of T-Cell activation by Fyn. IP3R releases Ca2+ from intracellular stores and triggers prolonged Ca2+ influx from the extracellular space through calcium release-activated calcium channel (CRAC). There are different classes of store-operated channels (SOCs). The class of SOCs found in T-Cells is the CRAC channel. It is distinguished from other SOCs primarily by its high Ca2+ selectivity. Ca2+ signals help to stabilize contacts between T-Cells and APC through changes in motility and cytoskeletal reorganization.Most TRP channels have a low Ca2+ selectivity. The influx of Ca2+ through specialized CRAC channels provides the persistent Ca2+ signal necessary to maintain NFAT proteins in the nucleus. The major Ca2+ and Calcineurin-responsive elements in the Nur77 promoter are binding sites for MEF2D. NFAT interacts with MEF2D and enhances its transcriptional activity, offering a plausible mechanism for activation of MEF2D by calcineurin. NFAT synergizes with MEF2D to recruit the co-activator p300 for the transcription of Nur77. Surprisingly, the enhancement of transcriptional activity of MEF2D by NFAT does not require its DNA-binding activity, suggesting that NFAT acts as a co-activator for MEF2D. Transient co-expression of p300, MEF2D, NFAT and constitutively active calcineurin is sufficient to recapitulate TCR signaling for the selective induction of the endogenous Nur77 gene. These results implicate NFAT as an important mediator of T-Cell apoptosis. Binding of Cabin1 to MEF2D suppresses MEF2D transcriptional activity. However, in the presence of a Ca2+ signal, calmodulin binds to Cabin1, freeing MEF2D to recruit the co-activator p300 for transcriptional activation of MEF2D target genes. The Cabin1-MEF2 interaction is required for proper MEF2D induction and phosphorylation after TCR signaling. The COOH-terminal region of Cabin1 interacts with MEF2D and calmodulin in a mutually exclusive manner. The interaction between Cabin1 and Caln is dependent on both Ca2+ and PKC activation, which results in Cabin1 hyperphosphorylation. As Cabin1 is found primarily in the nucleus in T-Cells, it interacts only with activated calcineurin that has translocated into the nucleus. Capn2 cleaves the calcineurin-binding domain of Cabin1 to activate calcineurin and elicit Ca2+-triggered cell death. Cabin1 cleavage and Caln activation are suppressed by Capn2 inhibitors. The cleavage of Cabin1 allows Cabin1 to be inactivated and dissociated from the calcineurin complex, leading to the activation of calcineurin. In unactivated T-Cells, MEF2D is bound to a transcriptional repressor complex consisting of Cabin1, HDAC1 and HDAC2. Upon TCR signaling and Ca2+ influx, activated calmodulin binds to Cabin1, releasing it from MEF2D, vacating the MADS/MEF2 domain for association with the coactivator p300. The Ca2+-dependent association and dissociation of two opposing classes of chromatin remodeling enzymes are responsible for tight control of Nur77 transcription.

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