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Stimulation of GTP Cyclohydrolase I by Phosphorylation Upon T Cell Activation
Author(s) -
Chen Wei,
Li Li,
Brod Torben,
Saeed Omar,
Dikalov Sergey,
Harrison David G.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.871.1
Subject(s) - biopterin , gtp cyclohydrolase i , tetrahydrobiopterin , phosphorylation , enos , t cell , chemistry , cell growth , endocrinology , medicine , microbiology and biotechnology , biochemistry , biology , enzyme , nitric oxide synthase , immunology , immune system
We have found that phosphorylation of GTP cyclohydrolase‐1 (GTPCH‐1), the rate‐limiting enzyme for BH 4 biosynthesis, increases its activity and BH 4 levels in endothelial cells. To determine if this occurs in non‐endothelial cells, we stimulated T cells in vitro (anti‐CD3) and in vivo (OVA immunization in OT2 mice). Naïve T cells had nearly undetectable levels of BH 4 and minimal expression of endothelial and inducible NOS. Anti‐CD3 stimulation robustly induced T cell eNOS and iNOS and increased biopterin to 5.4 pMol/mg protein. Biopterin induction was similar in CD4 and CD8 cells. Western blots showed that this was associated with GTPCH‐1 phosphorylation at S72. Pharmacological inhibition of casein kinase II prevented GTPCH‐1 phosphorylation and blunted the increase in T cell BH 4 . Inhibition of GTPCH‐1 with diaminohdroxypyimidine (DAHP, 500 μm) prevented T cell BH4 4 accumulation and increased T cell superoxide produciton, which was dependent on uncoupling of both eNOS and iNOS. GTPCH‐1 inhibition also promoted TH2 polarization in memory CD4 cells. OVA immunization in vivo confirmed a marked increase in T cell BH 4 . Thus, T cell activation is associated with GTPCH‐1 phosphorylation, which increases GTPCH‐1 activity and biopterin production. In inflammatory settings where BH 4 oxidation is favored, this could modulate T cell function. Supported by NIH R01 HL39006 and a VA Merit Grant.