Year: 2018
Type: article
Abstract: 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.
Source: Journal of Cell Science
DOI: 10.1242/jcs.223289
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: EGR-mediated STIM1-PMCA expression and function in T cell subsets, Structure and Function of Metabolic Filaments, Kinase-dependent Regulation of Metabolic Enzymes, Training Program in Cancer Research, The Role of Histone Chaperones in Histone Acetylation and Nucleosome Dynamics, G9000015149, G9000185824
OpenAlex ID: W2953262497