NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins.
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.
Huang
Guo N
GN
Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Huso
David L
DL
Bouyain
Samuel
S
Tu
Jianchen
J
McCorkell
Kelly A
KA
May
Michael J
MJ
Zhu
Yuwen
Y
Lutz
Michael
M
Collins
Samuel
S
Dehoff
Marlin
M
Kang
Shin
S
Whartenby
Katharine
K
Powell
Jonathan
J
Leahy
Daniel
D
Worley
Paul F
PF
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D000072233:Homer Scaffolding Proteins; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; D002352:Carrier Proteins; C000606616:HOMER3 protein, human; D000072233:Homer Scaffolding Proteins; C000606625:Homer2 protein, mouse; C000606627:Homer3 protein, mouse; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D011993:Recombinant Fusion Proteins; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin; D002118:Calcium