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Redundant expression but selective utilization of nuclear factor of activated T cells family members
L A Timmerman1, J I Healy, S N Ho
1The Howard Hughes Medical Institute, Stanford University, CA 94305, USA.
Abstract:
Nuclear factor of activated T cells (NF-AT) complexes regulate the induction of many early T cell activation molecules. Four related proteins can function as the cytoplasmic subunit of NF-AT, and their overlapping expression patterns and the mild phenotype of the NF-ATp null mice suggest that they may be functionally redundant. We characterized the distribution and activation of cytoplasmic NF-AT proteins in mature lymphocytes and found that NF-ATc, NF-ATp, and NF-AT4/x/c3 are co-expressed and co-regulated in mature T and B cells. Each protein forms independent DNA binding complexes, and at physiologic concentrations, NF-ATc and NF-ATp complexes out-compete NF-AT4/x/c3 for occupancy of NF-AT sites from the IL-2, IL-3/granulocyte-macrophage CSF, IL-4, and CD40 ligand genes. This predicts heavily redundant immune regulatory functions of NF-ATp and NF-ATc, but distinct activities for NF-AT4/x/c3. Additionally, Ab interaction with NF-ATp induces high affinity NF-kappaB site interaction, suggesting that nuclear partners may dramatically vary the specificity of the NF-AT family.
Insights
Nuclear factor of activated T cells (NF-AT) proteins, NF-ATc and NF-ATp, show redundant immune functions, while NF-AT4/x/c3 has distinct roles. Their interactions with nuclear partners modulate gene activation specificity.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Biology
Background:
- Nuclear factor of activated T cells (NF-AT) complexes are crucial for T cell activation.
- Four cytoplasmic NF-AT subunits exist, with overlapping expression suggesting functional redundancy.
Purpose of the Study:
- To investigate the distribution and activation of cytoplasmic NF-AT proteins in mature lymphocytes.
- To determine the functional redundancy and distinct roles of NF-AT family members.
Main Methods:
- Characterization of NF-AT protein expression and co-regulation in T and B cells.
- Analysis of DNA binding complex formation and competition for gene promoter occupancy.
Main Results:
- NF-ATc, NF-ATp, and NF-AT4/x/c3 are co-expressed and co-regulated in mature lymphocytes.
- NF-ATc and NF-ATp complexes competitively exclude NF-AT4/x/c3 from key gene regulatory sites.
- Antibody interaction with NF-ATp enhances NF-kappaB site interaction, indicating partner-dependent specificity.
Conclusions:
- NF-ATp and NF-ATc possess largely redundant immune regulatory functions.
- NF-AT4/x/c3 exhibits distinct immune regulatory activities.
- Nuclear partners significantly influence the specificity of NF-AT family proteins in gene regulation.