NFAT Binding and Regulation of T Cell Activation by the Cytoplasmic Scaffolding Homer Proteins

doi:10.1126/science.1151227

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Science 25 January 2008:
Vol. 319. no. 5862, pp. 476 - 481
DOI: 10.1126/science.1151227

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NFAT Binding and Regulation of T Cell Activation by the Cytoplasmic Scaffolding Homer Proteins

Guo N. Huang,¹^,2^* David L. Huso,³ Samuel Bouyain,⁴ Jianchen Tu,² Kelly A. McCorkell,⁵ Michael J. May,⁵ Yuwen Zhu,⁶ Michael Lutz,⁷ Samuel Collins,⁷ Marlin Dehoff,² Shin Kang,² Katharine Whartenby,⁷ Jonathan Powell,⁷ Daniel Leahy,⁴ Paul F. Worley²^,8

T cell receptor (TCR) and costimulatory receptor (CD28) signalscooperate in activating T cells, although understanding of howthese pathways are themselves regulated is incomplete. We foundthat Homer2 and Homer3, members of the Homer family of cytoplasmicscaffolding proteins, are negative regulators of T cell activation.This is achieved through binding of nuclear factor of activatedT cells (NFAT) and by competing with calcineurin. Homer-NFATbinding was also antagonized by active serine-threonine kinaseAKT, thereby enhancing TCR signaling via calcineurin-dependentdephosphorylation of NFAT. This corresponded with changes incytokine expression and an increase in effector-memory T cellpopulations in Homer-deficient mice, which also developed autoimmune-likepathology. These results demonstrate a further means by whichcostimulatory signals are regulated to control self-reactivity.

¹ Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Department of Oncology-Immunology/Hematopoiesis, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

^* Present address: Department of Molecular Biology, Universityof Texas Southwestern Medical Center, Dallas, TX 75235, USA.

These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: pworley{at}jhmi.edu

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