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Discs Large Homolog 1: Molecular Scaffolds Guiding T Cell Activation and Effector Function

  • Author(s): Silva, Oscar
  • Advisor(s): Miceli, Carrie
  • et al.
Abstract

Discs large homolog 1 (Dlgh1) is a scaffold protein that couples T cell receptor (TCR) engagement to signal transduction and cytoskeletal reorganization. Specifically, Dlgh1 directs Lck and ZAP70 kinase activity toward the selective activation of mitogen-activated protein kinase p38 and transcription factor NFAT. In addition, Dlgh1 controls actin polymerization, TCR and lipid raft clustering, and MTOC positioning during TCR engagement. The ability to selectively activate, integrate and tune these pathways may allow Dlgh1 to promote discrete cellular responses including: T cell differentiation, proliferation, cytokine production, cell-mediated cytotoxicity and memory generation. Therefore, understanding how Dlgh1 channels proximal TCR signals to specific downstream pathways to trigger distinct cellular responses in T cells requires 1) an understanding of how Dlgh1 is regulated by post-transcriptional and post-translational modifications, and 2) the development of a suitable Dlgh1 knockout (Dlgh1 KO) mouse model to assess Dlgh1 function in vivo.

Alternative splicing and phosphorylation of Dlgh1 are post-transcriptional and post-translational modifications that regulate Dlgh1 localization, expression and function. We found that alternative splicing of Dlgh1 in CD8+ effector T cells resulted in the expression of two distinct Dlgh1 protein variants: Dlgh1 AB and Dlgh1 B. Further, these two Dlgh1 variants served as molecular conduits to drive distinct cytotoxic T lymphocyte (CTL) responses. While both Dlgh1 AB and Dlgh1 B promoted p38-independent lytic factor degranulation, which required actin polymerization and the cytoskeletal regulator WASp, only Dlgh1 AB coupled Lck to p38-dependent production of proinflammatory cytokines. In addition, this CTL effector function was found to require Lck-mediated Dlgh1 AB tyrosine phosphorylation at tyrosine 222, suggesting that Dlgh1 AB tyrosine phosphorylation may provide a unique mechanism to specifically regulate p38-dependent functions in T cells. Lastly, we found that acute inducible knockout of Dlgh1 in mature peripheral T cells prevented optimal T cell activation and effector function in CD8+ T cells, while knockout of Dlgh1 in the germline or developing T cells had little or no effect on T cell function. Together, these data suggests that the developmental timing of Dlgh1 ablation may be critical for observing Dlgh1-dependent functional effects. We propose that T lymphocytes construct functionally unique Dlgh1 AB/Lck/p38 and Dlgh1/WASp complexes as a mechanism to specifically direct proximal TCR signals towards distinct cellular responses.

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