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Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function.


ABSTRACT: 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.

SUBMITTER: Lin JX 

PROVIDER: S-EPMC3551341 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function.

Lin Jian-Xin JX   Li Peng P   Liu Delong D   Jin Hyun Tak HT   He Jianping J   Ata Ur Rasheed Mohammed M   Rochman Yrina Y   Wang Lu L   Cui Kairong K   Liu Chengyu C   Kelsall Brian L BL   Ahmed Rafi R   Leonard Warren J WJ  

Immunity 20120401 4


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 con  ...[more]

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