|Title:||Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase||Authors:||Lin W.-C.
|Issue Date:||2018||Publisher:||Elsevier B.V.||Journal Volume:||24||Journal Issue:||10||Start page/Pages:||2733-27450000000||Source:||Cell Reports||Abstract:||
CTP synthase (CTPS) forms compartmentalized filaments in response to substrate availability and environmental nutrient status. However, the physiological role of filaments and mechanisms for filament assembly are not well understood. Here, we provide evidence that CTPS forms filaments in response to histidine influx during glutamine starvation. Tetramer conformation-based filament formation restricts CTPS enzymatic activity during nutrient deprivation. CTPS protein levels remain stable in the presence of histidine during nutrient deprivation, followed by rapid cell growth after stress relief. We demonstrate that filament formation is controlled by methylation and that histidine promotes re-methylation of homocysteine by donating one-carbon intermediates to the cytosolic folate cycle. Furthermore, we find that starvation stress and glutamine deficiency activate the GCN2/ATF4/MTHFD2 axis, which coordinates CTPS filament formation. CTPS filament formation induced by histidine-mediated methylation may be a strategy used by cancer cells to maintain homeostasis and ensure a growth advantage in adverse environments. Metabolic enzymes form membraneless compartments to adapt to environmental changes. Lin et al. demonstrate that histidine catabolism coupled with the folate cycle contributes to methionine synthesis, which promotes protein methylation. This post-translational modification in turn induces CTPS filament formation to preserve CTPS but reduces its enzymatic activity under starvation. ? 2018 The Authors
|ISSN:||2211-1247||DOI:||10.1016/j.celrep.2018.08.007||SDG/Keyword:||activating transcription factor 4; cytidine triphosphate synthase; folic acid; GCN2 protein; glutamine; histidine; homocysteine; methylenetetrahydrofolate dehydrogenase; MTHFD2 protein; tetramer; unclassified drug; cytidine triphosphate synthase; folic acid; histidine; homocysteine; ligase; protein serine threonine kinase; Article; cancer cell; cancer growth; cell compartmentalization; cell growth; cell stress; controlled study; cytosol; enzyme activity; homeostasis; human; human cell; priority journal; protein conformation; protein methylation; protein stability; animal; chemistry; genetics; metabolism; methylation; protein processing; Animals; Carbon-Nitrogen Ligases; Folic Acid; Histidine; Homocysteine; Humans; Methylation; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases
|Appears in Collections:||腦與心智科學研究所|
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