SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1.
XLP is caused by mutations affecting SAP, an adaptor that recruits Fyn to SLAM family receptors. SAP-deficient mice recapitulate features of XLP, including increased T cell activation and decreased humoral responses post-infection. SAP-deficient T cells also show increased TCR-induced IFN-gamma and decreased T(H)2 cytokine production. We demonstrate that the defect in IL-4 secretion in SAP-deficient T cells is independent of increased IFN-gamma production. SAP-deficient cells respond normally to polarizing cytokines, yet show impaired TCR-mediated induction of GATA-3 and IL-4. Examination of TCR signaling revealed normal Ca(2+) mobilization and ERK activation in SAP-deficient cells, but decreased PKC-theta recruitment, Bcl-10 phosphorylation, IkappaB-alpha degradation, and nuclear NF-kappaB1/p50 levels. Similar defects were observed in Fyn-deficient cells. SLAM engagement amplified PKC-theta recruitment in wt but not SAP- or Fyn-deficient cells, arguing that a SAP/Fyn-mediated pathway enhances PKC-theta/NF-kappaB1 activation and suggesting a role for this pathway in T(H)2 regulation.
Cannons
Jennifer L
JL
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Yu
Li J
LJ
Hill
Brenna
B
Mijares
Lilia A
LA
Dombroski
Derek
D
Nichols
Kim E
KE
Antonellis
Anthony
A
Koretzky
Gary A
GA
Gardner
Kevin
K
Schwartzberg
Pamela L
PL
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D015703:Antigens, CD; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics; D050990:GATA3 Transcription Factor; D006023:Glycoproteins / Q000502:physiology; D007136:Immunoglobulins / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D000074121:Protein Kinase C-theta; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011956:Receptors, Cell Surface; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D018418:Th2 Cells / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D015534:Trans-Activators; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta