Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function

  • Lin J
  • Li P
  • Liu D
 et al. 
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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. © 2012 Elsevier Inc..

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Authors

  • Jian Xin Lin

  • Peng Li

  • Delong Liu

  • Hyun Tak Jin

  • Jianping He

  • Mohammed Ata Ur Rasheed

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