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) signals
cooperate in activating T cells, although understanding of how
these pathways are themselves regulated is incomplete. We found
that Homer2 and Homer3, members of the Homer family of cytoplasmic
scaffolding proteins, are negative regulators of T cell activation.
This is achieved through binding of nuclear factor of activated
T cells (NFAT) and by competing with calcineurin. Homer-NFAT
binding was also antagonized by active serine-threonine kinase
AKT, thereby enhancing TCR signaling via calcineurin-dependent
dephosphorylation of NFAT. This corresponded with changes in
cytokine expression and an increase in effector-memory T cell
populations in Homer-deficient mice, which also developed autoimmune-like
pathology. These results demonstrate a further means by which
costimulatory signals are regulated to control self-reactivity.
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, University of 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
