T cell activation triggers reversible inosine-5'-monophosphate dehydrogenase assembly

Journal of Cell Science
Krisna C Duong-LyJeffrey R Peterson

Abstract

T cell-mediated adaptive immunity requires naïve, 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 Ca2+-dependent NFAT signaling, mTOR-mediated signaling and increased activity of the guanine nucleotide biosynthetic inosine-5'-monophosphate (IMP) dehydrogenase 1 and 2 enzymes (IMPDH1 and IMPDH2, hereafter 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 Ca2+ 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.

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Citations

May 29, 2020·Molecular Biology of the Cell·Jacqueline C SimonetJeffrey R Peterson
Dec 18, 2018·Frontiers in Immunology·S John CaliseEdward K L Chan
Aug 17, 2019·The Journal of Biological Chemistry·David Fernández-JustelRubén M Buey
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Aug 18, 2020·Autoimmunity Reviews·S John Calise, Edward K L Chan
Sep 30, 2021·Proceedings of the National Academy of Sciences of the United States of America·Eric M LynchJustin M Kollman

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