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


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.

SUBMITTER: Duong-Ly KC 

PROVIDER: S-EPMC6140318 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Duong-Ly Krisna C KC   Kuo Yin-Ming YM   Johnson Matthew C MC   Cote Joy M JM   Kollman Justin M JM   Soboloff Jonathan J   Rall Glenn F GF   Andrews Andrew J AJ   Peterson Jeffrey R JR  

Journal of cell science 20180905 17


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 Ca<sup>2+</sup>-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  ...[more]

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