Regulation of ribosomal RNA synthesis in T cells: requirement for GTP and Ebp1. Blood Nguyen, L. X., Lee, Y., Urbani, L., Utz, P. J., Hamburger, A. W., Sunwoo, J. B., Mitchell, B. S. 2015; 125 (16): 2519-2529

Abstract

Mycophenolic acid (MPA) is the active metabolite of Mycophenolate Mofeteil (MMF), an effective immunosuppressive drug. Both MPA and MMF are highly specific inhibitors of guanine nucleotide synthesis and of T cell activation. However, the mechanism by which guanine nucleotide depletion suppresses T cell activation is unknown. Depletion of GTP inhibits ribosomal RNA synthesis in T cells by inhibiting TIF-IA, a GTP-binding protein that recruits RNA Polymerase I to the ribosomal DNA promoter. TIF-IA-GTP binds the ErbB3 binding protein 1 (Ebp1) and together they enhance the transcription of proliferating cell nuclear antigen (PCNA). GTP binding by TIF-IA and Ebp1 phosphorylation by protein kinase C delta are both required for optimal PCNA expression. The PKC inhibitor Sotrastaurin markedly potentiates the inhibition of rRNA synthesis, PCNA expression, and T cell activation induced by MPA, suggesting that the combination of the two agents are more highly effective than either alone in inducing immunosuppression.

View details for DOI 10.1182/blood-2014-12-616433

View details for PubMedID 25691158