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N-domain–dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation

Nature Immunology volume 5, pages 208–215 (2004)Cite this article

Abstract

The N-terminal protein interaction domain (N-domain) of the signal transducer and activator of transcription-4 (STAT4) is believed to stabilize interactions between two phosphorylated STAT4 dimers to form STAT4 tetramers. Here, we show that nonphosphorylated STAT4 dimers form in vivo before cytokine receptor–driven activation. Mutations in the N-domain dimerization interface abolished assembly of nonphosphorylated STAT4 dimers and prevented STAT4 phosphorylation mediated by cytokine receptors. In addition, N-domain dimerization occurred for other STAT family members but was homotypic in character. This implies a conserved role for N-domain dimerization, which might include influencing interactions with cytokine receptors, favoring homodimer formation or accelerating formation of the phosphorylated STAT dimer.

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Figure 1: Analysis of STAT4 dimers produced by crystallographic symmetry to identify the physiologic dimer.
Figure 2: Mutational analysis of STAT4 N-domain dimerization.
Figure 3: Homotypic N-domain dimerization in the STAT family.
Figure 4: Formation of nonphosphorylated STAT4 dimers is mediated by N-domains.
Figure 5: Formation of nonphosphorylated STAT4 dimers is required for STAT4 activation and function.
Figure 6: N-domain dimerization–dependent STAT4 activation in vivo.

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Acknowledgements

The authors thank G.R. Stark (Lerner Research Institute, Cleveland, Ohio, USA) for providing the U3A cells, and J.D. Farrar (University of Texas Southwestern Medical Center, Dallas, Texas, USA) for helpful discussions.

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Authors and Affiliations

  1. Department of Pathology & Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    Naruhisa Ota, Tom J Brett, Theresa L Murphy, Daved H Fremont & Kenneth M Murphy

  2. Howard Hughes Medical Institute, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    Naruhisa Ota & Kenneth M Murphy

  3. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    Daved H Fremont

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Correspondence to Kenneth M Murphy.

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Ota, N., Brett, T., Murphy, T. et al. N-domain–dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation. Nat Immunol 5, 208–215 (2004). https://doi.org/10.1038/ni1032

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