Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function.
Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a-Stat5b double knockin (DKI) N-domain mutant mice in which STAT5 proteins form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined dimer versus tetramer consensus motifs. Whereas Stat5-deficient mice exhibited perinatal lethality, DKI mice were viable; thus, STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4(+)CD25(+) T cells, NK cells, and CD8(+) T cells, with impaired cytokine-induced and homeostatic proliferation of CD8(+) T cells. Moreover, DKI CD8(+) T cell proliferation after viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is critical for cytokine responses and normal immune function, establishing a critical role for STAT5 tetramerization in vivo.
Pubmed ID: 22520852 RIS Download
Animals | Binding Sites | CD4-Positive T-Lymphocytes | CD8-Positive T-Lymphocytes | Cell Proliferation | Cell Survival | Colitis | Cytokines | DNA-Binding Proteins | Gene Knock-In Techniques | Interleukin-2 Receptor alpha Subunit | Killer Cells, Natural | Lymphocyte Activation | Lymphocytic choriomeningitis virus | Mice | Mice, Transgenic | Protein Multimerization | STAT5 Transcription Factor | Signal Transduction