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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 Serguei,
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.lb187
Subject(s) - tetrahydrobiopterin , gtp cyclohydrolase i , biopterin , phosphorylation , enos , chemistry , t cell , cell growth , microbiology and biotechnology , medicine , endocrinology , biology , biochemistry , enzyme , nitric oxide synthase , immune system , immunology
Recently, we found that phosphorylation of GTP cyclohydrolase‐1 (GTPCH‐1), the rate‐limiting enzyme for BH4 biosynthesis, increases its activity and BH4 levels in endothelial cells. To determine if this occurs in non‐endothelial cells, we stimulated T cells both in vitro and in vivo. Naïve T cells had nearly undetectable levels of BH4 and minimal expression of either endothelial or inducible NOS. Anti‐CD3 stimulation robustly induced T cell eNOS and iNOS and increased biopterin from near undetectable levels 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 BH4. Inhibition of GTPCH‐1 with diaminohdroxypyimidine (DAHP, 500 μm) prevented T cell BH4 accumulation and increased T cell superoxide production, 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 BH4. Thus, T cell activation is associated with GTPCH‐1 phosphorylation, which increases GTPCH‐1 activity and biopterin production. In inflammatory settings where BH4 oxidation is favored, this could modulate T cell function. This study was supported by NIH grants PO1 HL58000 and RO1 HL39006.