Spatial-Temporal Mapping of the T Cell Receptor NF-kappaB Signaling Pathway

摘要

T lymphocytes are critical mediators of adaptive immunity that recognize antigen through the T cell receptor (TCR). Stimulation of the TCR leads to a complex signal transduction cascade resulting in the activation of the transcription factors NFAT, AP-1 and NF-kappaB. The activation of these transcription factors is a crucial step in T lymphocyte activation. TCR stimulation results in the spatial redistribution of several proteins involved in signal transduction to NF-kappaB. We find that the signaling intermediate Bcl10 forms cytoplasmic oligomers, called POLKADOTS, upon antigen stimulation. The formation of these structures requires the interaction between Bcl10 and MALT1 and is correlated with the activation of NF-kappaB. Our research shows that POLKADOTS are foci for functional interactions between signaling intermediates in TCR-mediated activation of NF-kappaB. In addition to forming POLKADOTS in the cytoplasm in response to antigen signals, a significant portion of cellular Bcl10 localizes to the nucleus in the steady state. Observations of high enrichment of Bcl10 in the nucleus of MALT lymphoma tumor cells suggest that Bcl10 nuclear localization may be actively regulated by signaling processes. Aberrant redistribution of Bcl10 to the nucleus in MALT lymphomas may contribute to tumorigenesis or pathogenesis. We show that Bcl10 is found in the nucleus of T lymphocytes, that this localization is regulated by PKCtheta, and that dose-dependent interactions with MALT1 mediate the nuclear export of Bcl10. We also show that the N-terminus of Bcl10 is essential for NF-kappaB activation, possibly by functioning as a transcriptional enhancer for NF-kappaB-responsive genes. These results may further suggest a pathogenic role for nuclear localization of Bcl10 in MALT lymphomas. In summary, through spatial-temporal analysis of Bcl10 subcellular localization and protein-protein interactions, we have further elucidated the role played by Bcl10 in health and in disease.