title: 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.
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Lin
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Delong
authors.initials: D
authors.lastname: Liu
authors.forename: Hyun Tak
authors.initials: HT
authors.lastname: Jin
authors.forename: Jianping
authors.initials: J
authors.lastname: He
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ata Ur Rasheed
authors.forename: Yrina
authors.initials: Y
authors.lastname: Rochman
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Kairong
authors.initials: K
authors.lastname: Cui
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Brian L
authors.initials: BL
authors.lastname: Kelsall
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
mesh_terms: D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D003092:Colitis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055879:Gene Knock-In Techniques; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000378:metabolism; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D008822:Mice, Transgenic; D055503:Protein Multimerization; D050799:STAT5 Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor