Diadenosine Tetraphosphate Hydrolase Is Part of the Transcriptional Regulation Network in Immunologically Activated Mast Cells

Abstract

We previously discovered that microphthalmia transcription factor (MITF) and upstream stimulatory factor 2 (USF2) each forms a complex with its inhibitor histidine triad nucleotide-binding 1 (Hint-1) and with lysyl-tRNA synthetase (LysRS). Moreover, we showed that the dinucleotide diadenosine tetraphosphate (

Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap4A Pathway in Immunologically Activated Mast Cells

“…Ap 4 A hydrolase phosphorylation seems to peak 15 min after activation. The positive correlation between phosphorylation status and Ap 4 A hydrolysis rate is in accordance with the Ap 4 A level, which drops rapidly 15 min after exposure to Ag (6).…”

“…Knockdown of Ap 4 A hydrolase modulated Ap 4 A accumulation, resulting in changes in the expression of the microphthalmia transcription factor (MITF) and upstream stimulating factor 2 (USF2) target genes. Thus, we provided concrete evidence establishing Ap 4 A as a second messenger in the regulation of gene expression (6).…”

“…Recently, we also provided evidence that Ap 4 A hydrolase is responsible for Ap 4 A degradation following immunological activation of mast cells and thus established Ap 4 A as a novel second messenger (6). In that study, we described the key role played by Ap 4 A hydrolase in regulation of both MITF and USF2 transcriptional activity.…”

“…In a previous work, we provided evidence that Ap 4 A hydrolase is responsible for Ap 4 A degradation following immunological activation of mast cells (6). We further described the critical role in transcriptional regulation played by Ap 4 A hydrolase as a component of our newly described lysyl tRNA synthetase (LysRS) biochemical pathway, which is activated upon immunological challenge.…”

Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription

“…Release of Hint-1 is specifically driven by antigen-IgE induced production of a signaling molecule, diadenosine tetraphosphate (AppppA or Ap 4 A) and consequent binding of Hint-1 to Ap 4 A. Simply increasing Ap 4 A (either by adding Ap 4 A to the cell medium or by knocking down in vivo Ap 4 A hydrolase) releases Hint-1 from MITF and activates transcription of MITF-targeted genes, establishing Ap 4 A as an important second messenger for transcriptional activation (Carmi-Levy et al, 2008; Lee et al, 2004). …”