NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins

Science. 319, 476 - 481 (2008)

Speaker: 謝家漪                            Time: 13:10~14:00, 03/19/ 2008

Commentator: 林以行 老師                  Place: Room 601

Abstract:

     T cells play a critical role in mediating immune responses. T-cell activation is mediated by T cell receptor (TCR) in combination with a costimulatory signal (e.g. CD28), but the understanding of how these pathways are regulated is not precisely defined. Homer family of cytoplasmicscaffolding proteins has been reported to distribute in various tissues and to act as scaffold and transduction molecules at the postsynapse. Homer3 was also shown to be recruited to the immune synapse. In this work authors first found that Homer3-deficient mice cause lymphocyte infiltration of multiple organs and hyperplasia in lymph nodes, indicating that Homer proteins might involve in T cell activation. Interleukine-2 (IL-2) is critical for T-cell activation. Hormer2 and Hormer3 (Hormer2/3) knockdown T cells increased the IL-2 promoter activity through the calcineurin-dependent NFAT (nuclear factor of activated T cells) dephosphorylation. From GST pull down assays, authors found that Hormer2/3 bound NFATc2 and competed with calcineurin for NFATc2 binding. Furthermore, the crystal structure of Homer3 showed that the predicted Akt phosphorylation sites are close to the putative NFATc2 binding surface. CD28 stimulation reduced the NFATc2-Hormer2/3 interaction in an Akt-dependent manner. Moreover, CD3 stimulation alone induced the higher IL-2 production in Homer2/3 deficiency T cells compared to wild-type T cells whereas CD3 plus CD28costimulation induced the comparable IL-2 production between Homer2/3 deficiency and wild type T cells. 

Finally, Homer deficiency mice increased effector-memory T-cell population and developed autoimmune-like phenotype. These data indicate a new function for Homer

proteins negatively regulating T-cell activation through NFAT.

References:

1. Kazuhiro Ishiguro, Ramnik Xavier. Homer-3 regulates activation of serum response element in T cells via its EVH1 domain. Blood: 103, 2248-2256 (2004)

2. R. S. Duncan, S. Y. Hwang, P. Koule. Effects of Vesl/Homer proteins on intracellular signaling. Exp. Biol. Med. (Maywood):230, 527-535 (2005).