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T cell activation triggers reversible inosine-5'-monophosphate dehydrogenase assembly
J Cell Sci. 2018 Sep 5;131(17)
PMID: 30154209    PMCID: PMC6140318    URL: https://www.ncbi.nlm.nih.gov/pubmed/30154209
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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.
1477-9137 Duong-Ly, Krisna C ORCID: http://orcid.org/0000-0002-4593-8145 Kuo, Yin-Ming ORCID: http://orcid.org/0000-0002-3036-1902 Johnson, Matthew C Cote, Joy M Kollman, Justin M ORCID: http://orcid.org/0000-0002-0350-5827 Soboloff, Jonathan ORCID: http://orcid.org/0000-0001-5192-1297 Rall, Glenn F ORCID: http://orcid.org/0000-0003-2717-3238 Andrews, Andrew J ORCID: http://orcid.org/0000-0002-2529-3714 Peterson, Jeffrey R ORCID: http://orcid.org/0000-0002-0604-718X R01 GM117907/GM/NIGMS NIH HHS/United States Journal Article England J Cell Sci. 2018 Aug 28. pii: jcs.223289. doi: 10.1242/jcs.223289.