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Duong-Ly KC, Kuo YM, Johnson MC, Cote JM, Kollman JM, Soboloff J, Rall GF, Andrews AJ, Peterson JR
T cell activation triggers reversible inosine-5'-monophosphate dehydrogenase assembly
J Cell Sci (2018) In process.
T cell-mediated adaptive immunity requires naive, unstimulated T cells to transition from a quiescent metabolic state into a highly proliferative state upon T cell receptor engagement. This complex process depends on transcriptional changes mediated by calcium-dependent NFAT signaling, mTOR-mediated signaling and increased activity of the guanine nucleotide biosynthetic enzyme inosine-5'-monophosphate (IMP) dehydrogenase (IMPDH). Inhibitors of these pathways serve as potent immunosuppressants. Unexpectedly, we discovered that all three pathways converge to promote the assembly of IMPDH protein into micron-scale macromolecular filamentous structures in response to T cell activation. Assembly is post-transcriptionally controlled by mTOR and the calcium influx regulator STIM1. Furthermore, IMPDH assembly and catalytic activity were negatively regulated by guanine nucleotide levels, suggesting a negative feedback loop that limits biosynthesis of guanine nucleotides. Filamentous IMPDH may be more resistant to this inhibition, facilitating accumulation of the higher GTP levels required for T cell proliferation.
Publication Date: 2018-09-05.
PMCID: PMC6140318
Last updated on Saturday, August 15, 2020