Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function.
Lin, Jian-Xin; Li, Peng; Liu, Delong; Jin, Hyun Tak; He, Jianping; Rasheed, Mohammed Ata Ur; Rochman, Yrina; Wang, Lu; Cui, Kairong; Liu, Chengyu; Kelsall, Brian L.; Ahmed, Rafi; Leonard, Warren J.
[Article]
Immunity.
36(4):586-599, April 2012.
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: 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.
Highlights: [black up pointing small triangle] Spacing between nonconsensus GAS motifs is critical for STAT5 tetrameric binding
[black up pointing small triangle] STAT5 tetramers regulate the expression of a subset of cytokine-induced genes
[black up pointing small triangle] Cytokine-induced and homeostatic CD8 T cell proliferation require STAT tetramers
[black up pointing small triangle] STAT5 tetramers are critical for normal Treg cell function in vivo
(C) 2012Elsevier, Inc.